Compositions and methods for transdermal oxybutynin therapy

ABSTRACT

The present invention provides compositions and methods for administering oxybutynin while minimizing the incidence and or severity of adverse drug experiences associated with oxybutynin therapy. In one aspect, these compositions and methods provide a lower plasma concentration of oxybutynin metabolites, such as N-desethyloxybutynin, which is presumed to be contributing at least in part to some of the adverse drug experiences, while maintaining sufficient oxybutynin plasma concentration to benefit a subject with oxybutynin therapy. The invention also provides isomers of oxybutynin and its metabolites that meet these characteristics of minimized incidence and/or severity of adverse drug experiences, and maintenance of beneficial and effective therapy for overactive bladder. In some aspects, the composition may be presented in the form of an unoccluded or free form topically administered gel.

PRIORITY

This application is a continuation of U.S. patent application Ser. No.12/236,585, filed Sep. 24, 2008, which is a divisional application ofU.S. patent application Ser. No. 11/645,076, filed Dec. 21, 2006, nowissued as U.S. Pat. No. 8,241,662, which in turn is a continuation ofU.S. patent application Ser. No. 10/913,019, filed Aug. 6, 2004, nowissued as U.S. Pat. No. 7,179,483, which is a continuation-in-part ofU.S. patent application Ser. No. 10/286,381, filed Nov. 11, 2002, nowissued as U.S. Pat. No. 7,029,694, which is a continuation-in-part ofU.S. patent application Ser. No. 10/098,752, filed Mar. 15, 2002, nowissued as U.S. Pat. No. 6,743,441, which is a continuation of U.S.patent application Ser. No. 09/559,711, filed Apr. 26, 2000, nowabandoned, each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for minimizingadverse drug experiences associated with oxybutynin therapy.Accordingly, this invention covers the fields of pharmaceuticalsciences, medicine and other health sciences.

BACKGROUND OF THE INVENTION

Oral oxybutynin therapy is currently used for treating various forms ofoveractive bladder and urinary incontinence. Particularly, oxybutynineffectively treats neurogenically caused bladder disorders. Relief fromsuch disorders is attributed to the anticholinergic and antispasmodicaction which oxybutynin imparts to the parasympathetic nervous systemand the urinary bladder detrusor muscle.

It is generally believed that, while this anticholinergic activitycontributes to oxybutynin's clinical usefulness, it also contributes tocertain uncomfortable adverse drug experiences such as dry mouth,dizziness, blurred vision, and constipation. More specifically, theseexperiences have been generally attributed to the presence and amount ofactive metabolites of oxybutynin, for example, N-desethyloxybutynin. Theabove-referenced adverse drug experiences are observed in a majority ofpatients using current oxybutynin formulations. In some cases, theseadverse experiences are severe enough to persuade the patient todiscontinue treatment.

In view of the foregoing, compositions and methods for administeringoxybutynin to help minimize the incidence and/or severity of theabove-described adverse drug experiences are extremely desirable.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides methods of minimizing anadverse drug experience associated with oxybutynin therapy whichcomprises the step of administering a pharmaceutical compositioncomprising oxybutynin to a subject such that the ratio of area under theplasma concentration-time curve (AUC) of oxybutynin to an oxybutyninmetabolite is about 0.5:1 to about 5:1. The adverse drug experience maybe any adverse experience resulting from administration of oxybutynin,for example, anticholinergic, and/or antimuscarinic in nature.

Specific examples of known oxybutynin adverse experiences include butare not limited to: gastrointestinal/genitourinary experiences, nervoussystem experiences, cardiovascular experiences, dermatologicalexperiences, and opthalmic experiences, among others.

Oxybutynin has a chiral molecular center, leading to the presence of(R)- and (S)-isomers. When metabolized, oxybutynin gives rise tometabolites such as N-desethyloxybutynin, which may also be present as(R)- and (S)-isomers or a combination thereof. The method of the presentinvention specifically encompasses each isomer for both oxybutynin andits any corresponding metabolites. For example, in one aspect, the meanplasma AUC ratio of (R)-oxybutynin to (S)-oxybutynin is about 0.7:1. Inanother aspect, the mean AUC ratio of (R)—N-desethyloxybutynin to(R)-oxybutynin is from about 0.4:1 to about 1.6:1. In one aspect, thismean AUC ratio may be about 1:1. In another aspect, the mean AUC ratioof (R)—N-desethyloxybutynin to (S)—N-desethyloxybutynin is from about0.5:1 to about 1.3:1. For example, this mean AUC ratio may be about0.9:1. In another aspect, the metabolite may have a mean peak plasmaconcentration of less than about 8 ng/ml.

A pharmaceutical composition for administering oxybutynin to a subjectis also provided, comprising oxybutynin that provides an AUC ratio ofoxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1.

Delivery formulations useful in conjunction with the method of thepresent invention include but are not limited to: oral, parenteral,transdermal, inhalant, or implantable formulations. In one aspect of theinvention, the delivery formulation may be a transdermal deliveryformulation. In a more specific aspect, the delivery formulation may bea gel formulation that is topically administered to the skin in anunoccluded, or free form manner.

The composition of the present invention may include a pharmaceuticallyacceptable carrier, and other ingredients as dictated by the particularneeds of the specific dosage formulation. Such ingredients are wellknown to those skilled in the art. See for example, Gennaro, A.Remington: The Science and Practice of Pharmacy 19^(th) ed. (1995),which is incorporated by reference in its entirety. For example, atransdermal formulation may include, but is not limited to, permeationenhancers, anti-irritants, adhesion adjusters, and combinations thereof.

In one aspect, the formulation of the present invention may be anoxybutynin gel formulation for topical application. Such a gel mayinclude a therapeutically effective amount of oxybutynin and a gelcarrier, wherein the formulation has a pH of from about 4 to about 11and wherein the oxybutynin is present as an oxybutynin free base, apharmaceutically acceptable oxybutynin salt, or a mixture thereof, andwherein the formulation is prepared for unoccluded topical applicationto a skin surface. In another aspect, the pH of the formulation may befrom about 4 to about 11. In a further aspect, the pH of the formulationmay be from about 5 to about 11. In yet a further aspect, the pH of theformulation may be from about 6 to about 11. In an additional aspect,the pH of the formulation may be from about 4 to about 10. In anotheraspect, the pH of the formulation can be from about 5 to about 10. In anadditional aspect, the pH of the formulation can be from about 6 toabout 10. In a more detailed aspect, the pH of the formulation may beabout 6. In yet another detailed aspect of the invention, the pH of theformulation is about 9.

According to another aspect of the invention, a gel formulation fortopical application is presented which includes a therapeuticallyeffective amount of oxybutynin in a gel carrier, which upon unoccludedtopical administration, is sufficient to provide an oxybutynin skinpermeation rate of at least about 10 ug/cm² over a period of at leastabout 24 hours.

In a further aspect of the invention, a gel formulation for topicalapplication is presented which includes a therapeutically effectiveamount of oxybutynin in a gel carrier, which upon unoccluded topicaladministration, is sufficient to achieve an oxybutynin plasmaconcentration of at least about 0.5 ng/ml within at least about 3 hoursafter initiation of administration.

In another aspect of the invention, a gel formulation is provided fortopical application that includes a therapeutically effective amount ofoxybutynin in a gel carrier, which upon unoccluded topicaladministration, is sufficient to achieve an oxybutynin plasmaconcentration that is from about 0.5 to about 5 times an oxybutyninmetabolite plasma concentration.

In an additional aspect of the invention, a gel formulation for topicalapplication is provided that includes a therapeutically effective amountof oxybutynin in a gel carrier, which upon unoccluded topicaladministration, is sufficient to achieve a therapeutically effectiveoxybutynin concentration and a maximum oxybutynin metabolite plasmaconcentration of less than about 8 ng/ml.

In addition to the compositions recited herein, the present inventionadditionally encompasses a method for treating neurogenic bladderdisorders in a subject which includes topically applying a gelformulation as recited herein to a skin surface of the subject.Moreover, the present invention includes a method of minimizing adverseside effects associated with oxybutynin therapy includes applying anoxybutynin gel formulation as recited herein to a skin surface asubject.

In another aspect of the present invention, an oxybutynin gelformulation for topical administration is provided, having atherapeutically effective amount of oxybutynin in a gel carrier, whichupon unoccluded topical administration, is sufficient to provide aplasma AUC ratio of oxybutynin serum level to an oxybutynin metaboliteserum level from about 0.75:1 to about 3:1. In another aspect, the ratiomay be from about 0.98:1 to about 2:1. In a further aspect, theoxybutynin serum concentration may be greater than an oxybutyninmetabolite serum concentration.

In yet another aspect of the present invention, a method of treatingwith oxybutynin a subject having overactive bladder is provided. Themethod may include the step of topically administering to a subject anoxybutynin gel formulation, which upon unoccluded topicaladministration, is sufficient to provide a plasma AUC ratio ofoxybutynin serum level to an oxybutynin metabolite serum level fromabout 0.75:1 to about 3:1, in order to minimize an anticholinergic orantimuscarinic adverse drug experience associated with oxybutynintreatment therapy.

There has thus been outlined, rather broadly, the more importantfeatures of the invention so that the detailed description thereof thatfollows may be better understood, and so that the present contributionto the art may be better appreciated. Other features of the presentinvention will become clearer from the following detailed description ofthe invention, taken with the accompanying drawings and claims, or maybe learned by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured following a 5 mgoxybutynin immediate-release oral dosage formulation.

FIG. 2 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured upon transdermaladministration according to the present invention, spanning a time frominitial oxybutynin administration to 24 hours therefrom.

FIG. 3 is a graphical representation of total oxybutynin andN-desethyloxybutynin plasma concentrations measured upon transdermaladministration according to the present invention, spanning a time frominitial oxybutynin administration to 96 hours therefrom, and for anadditional 12 hours following the removal of the transdermal system at96 hours.

FIG. 4 is a graphical representation of the results of treating asubject with overactive bladder with transdermal administration ofoxybutynin in accordance with the present invention, as compared totreatment with a 5 mg immediate-release oxybutynin oral tablet byrecording the number of episodes of urinary incontinence.

FIG. 5 is a graphical representation of the anticholinergic adverseexperiences reported by subjects receiving treatment for overactivebladder with a transdermal administration of oxybutynin in accordancewith the present invention, as compared to treatment with a 5 mgoxybutynin immediate-release oral tablet.

FIG. 6 is a graphical representation of the plasma concentrationsproduced for the (R) and (S) isomers of both oxybutynin andN-desethyloxybutynin upon administering a 5 mg immediate-release oraltablet.

FIG. 7 is a graphical representation of the plasma concentrations of (R)and (S) isomers for both oxybutynin and N-desethyloxybutynin achieved bytransdermal administration in accordance with the present invention.

FIG. 8 is a graphical representation of the plasma concentrations ofoxybutynin and N-desethyloxybutynin following topical application of4.4% oxybutynin gel in accordance with the present invention.

FIG. 9 is a graphical representation of the plasma concentrations ofoxybutynin and N-desethyloxybutynin following topical application of13.2% oxybutynin gel in accordance with the present invention.

FIG. 10 is a graphical representation of the plasma concentrations ofoxybutynin and N-desethyloxybutynin following single and repeatedtopical application of 4.4% oxybutynin gel in accordance with thepresent invention.

FIG. 11 is a graphical representation of the plasma concentrations ofoxybutynin and N-desethyloxybutynin following single and repeatedtopical application of 4.4% oxybutynin gel in accordance with thepresent invention.

FIG. 12 is a graphical representation of the plasma concentrations ofoxybutynin and N-desethyloxybutynin following topical application of4.4% oxybutynin gel to a 400 cm² patch[AREA?] of skin in accordance withthe present invention.

FIG. 13 is a graphical representation of the plasma concentrations ofoxybutynin and N-desethyloxybutynin following topical application of13.2% oxybutynin gel to a 400 cm² patch of skin area in accordance withthe present invention.

DETAILED DESCRIPTION A. Definitions

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set forthbelow.

The singular forms “a,” “an,” and, “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“an adhesive” includes reference to one or more of such adhesives, andreference to “an excipient” includes reference to one or more of suchexcipients.

“Oxybutynin” refers to the compound having the general structure of:

The oxybutynin addition salt, oxybutynin HCl, is listed in the MerckIndex, entry no. 7089, at page 1193, 12th ed., (1996, and is known byseveral IUPAC names such as a-Cyclohexyl-hydroxy-benzenacetic acid4-(diethylamino)-2-butynyl ester hydrochloride; a-phenylcyclohexaneglycolic acid 4-(diethylamino)-2-butynyl ester hydrochloride;and 4-di ethylamino-2-butynylphenylcyclohexylglycolate hydrochloride.“Oxybutynin” as used herein includes oxybutynin free base, its acidaddition salts such as oxybutynin HCl, their analogs and relatedcompounds, isomers, polymorphs, and prodrugs thereof. It is generallyknown that oxybutynin may exist in one or both of its isomeric forms,known as the (R)- and (S)-isomers, or a mixture of these two isomers.These isomeric forms and their mixtures are within the scope of thisinvention. Notably, in some portions of the present application, thecontext may clearly dictate the specific form of oxybutynin, such asoxybutynin chloride, even though only “oxybutynin” is recited.

“Administration,” and “administering” refer to the manner in which adrug is presented to a subject. Administration can be accomplished byvarious art-known routes such as oral, parenteral, transdermal,inhalation, implantation, etc. Thus, an oral administration can beachieved by swallowing, chewing, sucking of an oral dosage formcomprising the drug. Parenteral administration can be achieved byinjecting a drug composition intravenously, intra-arterially,intramuscularly, intrathecally, or subcutaneously, etc. Transdermaladministration can be accomplished by applying, pasting, rolling,attaching, pouring, pressing, rubbing, etc., of a transdermalpreparation onto a skin surface. These and additional methods ofadministration are well-known in the art.

The term “non-oral administration” represents any method ofadministration in which a drug composition is not provided in a solid orliquid oral dosage form, wherein such solid or liquid oral dosage formis traditionally intended to substantially release and or deliver thedrug in the gastrointestinal tract beyond the mouth and/or buccalcavity. Such solid dosage forms include conventional tablets, capsules,caplets, etc., which do not substantially release the drug in the mouthor in the oral cavity.

It is appreciated that many oral liquid dosage forms such as solutions,suspensions, emulsions, etc., and some oral solid dosage forms mayrelease some of the drug in the mouth or in the oral cavity during theswallowing of these formulations. However, due to their very shorttransit time through the mouth and the oral cavities, the release ofdrug from these formulations in the mouth or the oral cavity isconsidered deminimus or insubstantial. Thus, buccal patches, adhesivefilms, sublingual tablets, and lozenges that are designed to release thedrug in the mouth are non-oral compositions for the present purposes.

In addition, it is understood that the term “non-oral” includesparenteral, transdermal, inhalation, implant, and vaginal or rectalformulations and administrations. Further, implant formulations are tobe included in the term “non-oral,” regardless of the physical locationof implantation. Particularly, implantation formulations are known whichare specifically designed for implantation and retention in thegastrointestinal tract. Such implants are also considered to be non-oraldelivery formulations, and therefore are encompassed by the term“non-oral.”

The term “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans, and other animals such as horses,pigs, cattle, dogs, cats, rabbits, and aquatic mammals.

As used herein, the terms “formulation” and “composition” are usedinterchangeably. The terms “drug” and “pharmaceutical” are also usedinterchangeably to refer to a pharmacologically active substance orcomposition. These terms of art are well-known in the pharmaceutical andmedicinal arts.

The term “transdermal” refers to the route of administration thatfacilitates transfer of a drug through a skin surface wherein atransdermal composition is administered to the skin surface.

The term “skin” or “skin surface” is meant to include not only the outerskin of a subject comprising one or more of epidermal layers, but alsoto include mucosal surfaces to which a drug composition may beadministered. Examples of mucosal surfaces include the mucosa of therespiratory (including nasal and pulmonary), oral (mouth and buccal),vaginal, and rectal cavities. Hence the terms “transdermal” mayencompass “transmucosal” as well.

The terms “enhancement”, or “permeation enhancement,” mean an increasein the permeability of the skin, to a drug, so as to increase the rateat which the drug permeates through the skin. Thus, “permeationenhancer” or simply “enhancer” refers to an agent, or mixture of agentsthat achieves such permeation enhancement.

An “effective amount” of an enhancer means an amount effective toincrease penetration of a drug through the skin, to a selected degree.Methods for assaying the characteristics of permeation enhancers arewell-known in the art. See, for example, Merritt et al., DiffusionApparatus for Skin Penetration, J. of Controlled Release 61 (1984),incorporated herein by reference in its entirety. By “effective amount”or “therapeutically effective amount,” or similar terms is meant anon-toxic but sufficient amount of a drug, to achieve therapeuticresults in treating a condition for which the drug is known to beeffective. The determination of an effective amount is well-within theordinary skill in the art of pharmaceutical and medical sciences. Seefor example, Curtis L. Meinert & Susan Tonascia, Clinical Trials:Design, Conduct, and Analysis, Monographs in Epidemiology andBiostatistics, vol. 8 (1986).

By the term “mean,” “mathematical mean,” “average,” or similar termswhen used in conjunction with the recitation of a number, or numbers,means the sum of all the individual observations or items of a sampledivided by the number of items in the sample.

By the term “matrix”, “matrix system”, or “matrix patch” is meant acomposition comprising an effective amount of a drug dissolved ordispersed in a polymeric phase, which may also contain otheringredients, such as a permeation enhancer and other optionalingredients. This definition is meant to include embodiments whereinsuch polymeric phase is laminated to a pressure sensitive adhesive orused within an overlay adhesive.

A matrix system may also comprise an adhesive layer having animpermeable film backing attached onto the distal surface thereof and,before transdermal application, a release liner on the proximal surfaceof the adhesive. The film backing protects the polymeric phase of thematrix patch and prevents release of the drug and/or optionalingredients to the environment. The release liner functions similarly tothe impermeable backing, but is removed from the matrix patch prior toapplication of the patch to the skin as defined above. Matrix patcheswith the above-described general characteristics are known in the art oftransdermal delivery. See, for example, U.S. Pat. Nos. 5,985,317,5,783,208, 5,626,866, 5,227,169, which are incorporated by reference intheir entirety.

“Topical formulation” means a composition in which the drug may beplaced for direct application to a skin surface and from which aneffective amount of the drug is released. Such formulations may includegels, lotions, cremes or other formulations which are applied to theskin. In some aspects, such formulations may be applied to the skin inan unoccluded form without additional backing, structures or devices.

As used herein, “unoccluded” and “non-occluded” may be usedinterchangeably, and refer to application of a topical formulation tothe skin without the use of a supporting or otherwise associatedstructure. In other words, the topical formulation is applied to theskin in a free form, which is sufficient to effect transdermal deliveryof oxybutynin without the use of structures, such as a backing member,etc.

As used herein, “gel” refers to a composition including a compound ofhigh molecular weight which acts as a thickening agent to produce asemisolid or suspension-type formulation. The thickening or gellingagents may be hydrophobic or hydrophilic and are generally polymeric innature. Gels which incorporate hydrophilic polymers are typically knownin the art as hydrogels. Gels may include a variety of additionalcomponents such as, but not limited to, active agents, excipients,solvents, emulsifiers, chelating agents, surfactants, emollients,permeation enhancers, preservatives, antioxidants, lubricants, pHadjusters, adjuvants, dyes, and perfumes.

“Adverse drug experience” refers to any adverse event associated withthe use of a drug in a subject, including the following: an adverseevent occurring in the course of the use of a drug product inprofessional practice; an adverse event occurring from drug overdosewhether accidental or intentional; an adverse event occurring from drugabuse; an adverse event occurring from drug withdrawal; and any failureof expected pharmacological action. The adverse drug experience may leadto a substantial disruption of a person's ability to conduct normal lifefunctions. In some instances, the adverse drug experience may be seriousor life threatening.

While some of the adverse drug experiences may be expected, in someinstances, such experiences may be unexpected. “Unexpected,” refers toan adverse drug experience that has not been previously catalogued by aresponsible governmental agency (such as the Food and DrugAdministration of the United States) and or not provided in the currentlabeling for the drug product.

The unexpected adverse experiences may include events that may besymptomatically and pathophysiologically related to a known event, butdiffer from the event because of greater severity or specificity. Forexample, under this definition, hepatic necrosis would be unexpected (byvirtue of greater severity) if the known event is elevated hepaticenzymes or hepatitis. Similarly, cerebral thromboembolism and cerebralvasculitis would be unexpected (by virtue of greater specificity) if theknown event is cerebral vascular accidents. For a more comprehensivedefinition and description of adverse drug experience, see 21 C.F.R.§314.80, which is incorporated by reference in its entirety.

The majority of the adverse experiences associated with oxybutynintherapy may be categorized as anticholinergic, and/or antimuscarinic.Certain adverse experiences associated with oxybutynin have beencategorized in the Physician's Desk Reference as cardiovascularexperiences, gastrointestinal/genitourinary experiences, dermatologicexperiences, nervous system experiences, and opthalmic experiences,among others.

Examples of cardiovascular adverse experiences include but are notlimited to: palpitations, tachycardia, vasodilation, and combinationsthereof. Examples of dermatologic adverse experiences include but arenot limited to: decreased sweating, rashes, and combinations thereof.Examples of gastrointestinal/genitourinary adverse experiences includebut are not limited to: constipation, decreased gastrointestinalmotility, dry mouth, nausea, urinary hesitance and retention, andcombinations thereof. Examples of nervous system adverse experiencesinclude but are not limited to: asthenia, dizziness, drowsiness,hallucinations, insomnia, restlessness, and combinations thereof.Examples of opthalmic adverse experiences include but are not limitedto: amblyopia, cycloplegia, decreased lacrimation, mydriasis, andcombinations thereof. Examples of other adverse experiences include butare not limited to: impotence and suppression of lactation. A morecomprehensive listing of adverse experiences may be found in thelabeling of the oxybutynin formulations as provided by the regulatoryagencies.

The term “minimize” and its grammatical equivalents refer to a reductionin the frequency and or severity of one or more adverse drug experiencesin a given subject or subject population. It is appreciated that thesubject population may be of necessity much smaller in size than thegeneral population that may be exposed to the drug and/or its adverseexperiences.

It is also appreciated that the results obtained from methods fordetermining the reduction in the frequency and/or severity of adversedrug experiences may be subject to variables such as intra-subject andinter-subject factors. However, it is also appreciated that certainscientifically accepted methods can be used to conduct the studies andthat the results from such studies are statistically reliable. Suchmethods and interpretation of the results from such methods arewell-known in the art. See, for example, Robert R. Sokal & F. JamesRohlf, Biometry: The Principles and Practice of Statistics in BiologicalResearch, 2^(nd) ed. (1969), which is incorporated by reference in itsentirety.

The phrase “area under the curve”, “area under the plasmaconcentration-time curve,” or similar terms are well known in thepharmaceutical arts. These values are calculated by plotting a graphwith data from plasma concentration of a given drug or its metabolitesas a function of time, with the X-axis generally representing time andthe Y-axis generally representing plasma concentration. The area underthe line formed by joining the various data points is then integratedinto a numerical value. See for example, Milo Gibaldi & Donald Perrier,PharmacoKinetics, 2^(nd) ed. (1982). The AUC multiplied by the clearanceor total body clearance (CL), of the substance being measured, thusprovides an estimate of the total amount, or dose, of the substancebeing measured (the drug or one or more of its metabolites). Plasmaconcentrations, AUC, and CL may be subject to inter- and intra-subjectvariation due to physiological and/or environment factors present inindividual subjects during the administration of medicinal agents, suchas oxybutynin, in various formulation and/or compositions. Therefore,individual and mean values may be subject to variability, however, thegeneral trends and relationships are preserved and reproducible.

Concentrations, amounts, solubilities, and other numerical data may bepresented herein in a range format. It is to be understood that suchrange format is used merely for convenience and brevity and should beinterpreted flexibly to include not only the numerical values explicitlyrecited as the limits of the range, but also to include all theindividual numerical values or sub-ranges encompassed within that rangeas if each numerical value and sub-range is explicitly recited.

For example, a concentration range of 0.1 to 5 ng/ml should beinterpreted to include not only the explicitly recited concentrationlimits of 0.1 ng/ml and 5 ng/ml, but also to include individualconcentrations such as 0.2 ng/ml, 0.7 ng/ml, 1.0 ng/ml, 2.2 ng/ml, 3.6ng/ml, 4.2 ng/ml, and sub-ranges such as 0.3-2.5 ng/ml, 1.8-3.2 ng/ml,2.6-4.9 ng/ml, etc. This interpretation should apply regardless of thebreadth of the range or the characteristic being described.

B. The Invention

As described above, the present invention provides compositions andmethods for administering oxybutynin. These compositions and methods areshown to have minimized the incidence and/or severity of an adverseexperience associated with oxybutynin administration, while providingsufficient oxybutynin to impart a therapeutic benefit. Without intendingto be bound to any specific theory, it is believed that the minimizationof adverse experiences is due in part to the reduction in plasmaconcentration of metabolites of oxybutynin such as N-desethyloxybutyninby the present compositions and methods when compared to conventionaloral administration. The phrase “conventional oral administration” ismeant to include the oral formulations as defined supra, and includesfor example, an immediate-release or sustained-release oral tabletcomprising oxybutynin. One such conventional oral formulation isavailable as a 5 mg immediate-release oral tablet.

1) The Pharmacokinetic Aspects Associated with Total Drug and MetabolitePlasma Concentrations

The desired pharmacokinetic attributes such as reduced plasmaconcentrations of oxybutynin metabolites may be achieved by, interalia: 1) reducing the amount of oxybutynin administered, 2) reducing therate at which oxybutynin becomes available for metabolism by the body,and/or 3) avoiding or minimizing first-pass hepatic and/or intestinalmetabolism of oxybutynin. Using a non-oral route of administration isone way to achieve one or more of these objectives. Alternatively, anoral dosage form could be designed to mimic a non-oral administration toachieve the plasma concentrations and other pharmacokinetic datadescribed herein.

A clinical study has been performed to demonstrate one embodiment of thepresent invention. A cross-over clinical study in 16 healthy volunteerswas conducted to compare plasma concentrations and pharmacokinetics ofoxybutynin and one of its metabolites, N-desethyloxybutynin, and theirrespective (R)- and (S)-enantiomeric components.

Conventional oral dosage forms of oxybutynin, such as the 5 mgoxybutynin tablet used in the present study produce significantly higherplasma concentrations of oxybutynin metabolites such asN-desethyloxybutynin as compared to the parent drug (See FIG. 1). Themean AUC ratio of metabolite to oxybutynin concentration is about 10:1in the majority of cases, and is generally greater than about 5:1.

In contrast, when oxybutynin is administered in a non-oral, slow releasecomposition, such as the transdermal composition embodiment of thepresent invention, the mean AUC ratio of the metabolite(N-desethyloxybutynin) to oxybutynin is much lower. Generally, the meanAUC ratio of oxybutynin metabolite (N-desethyloxybutynin) to oxybutyninis less than about 2:1. Further, in the majority of instances, the ratiois less than about 1.2:1, and often, the ratio is approximately 0.9:1.(See FIG. 3).

Additionally, the mean N-desethyloxybutynin plasma concentration isgenerally less than about 8 ng/ml, and in the majority of instances isless than about 5 ng/ml. Often the mean is less than about 3 ng/ml.

2) Pharmacokinetic Aspects of Isomers

The present inventors have investigated further into the aspectsdescribed above and have discovered that the present formulations andmethods provide significantly reduced levels of particular isomers ofcertain oxybutynin metabolites and that these reduced levels ofmetabolite isomers correlate to the minimized adverse drug experiencesdescribed above.

It is generally known that oxybutynin exists as an (R)- or as an(S)-isomer or a combination thereof. Particularly, (R)-oxybutynin hasbeen thought to be the more active of the two isomers, as indicated byanimal pharmacological studies using isolated tissues. See for example,Kachur J F, Peterson J S, Carter J P, et al. J. Pharm Exper. Ther. 1988;247:867-872; see also, Noronha-Blob L, Kachur J F. J. Pharm. Exper.Ther. 1990; 256:56-567. As such, (R)—N-desethyloxybutynin, being themore active constituent of the total amount of metabolite, maycontribute more significantly to adverse drug experiences such asanticholinergic adverse effects than the less active(S)—N-desethyloxybutynin. See for example, U.S. Pat. No. 5,677,346,which is incorporated by reference in its entirety.

Accordingly, plasma concentrations were measured for both (R)- and(S)-oxybutynin and the corresponding isomers of one of its metabolites,N-desethyloxybutynin during the clinical study mentioned above. Thetests performed revealed that the present invention results insignificantly lower (R)—N-desethyloxybutynin plasma concentrationscompared to conventional oral dosage forms and administration methods.

FIG. 6 shows the plasma concentration profile from the conventionaloxybutynin 5 mg oxybutynin oral tablet. As can be seen,(R)—N-desethyloxybutynin is present in the greatest concentration, andis several times the concentration of both (R)- and (S)-oxybutynin. Themean AUC ratio of the (R)—N-desethyloxybutynin to (R)-oxybutynin, thetwo most active isomers, following oral administration is about 17:1. Inaddition, the mean AUC ratio of (R)—N-desethyloxybutynin to(S)—N-desethyloxybutynin is about 1.5:1, and the mean AUC ratio of(R)-oxybutynin to (S)-oxybutynin is about 0.6:1. These ratios of AUCconsistently show that orally administered oxybutynin results in arelatively low amount of therapeutically active (R)-oxybutynin given thelarge total dose of racemic oxybutynin. Further, the oral dose resultsin a relatively large amount of (R)—N-desethyloxybutynin, the moietymost likely to be responsible for causing some or many of the adversedrug experiences.

In contrast, FIG. 7 shows the (R)- and (S)-isomer plasma profiles of thepresent invention which were achieved during the clinical study bynon-orally delivered oxybutynin. The mean AUC ratio of (R)-oxybutynin to(S)-oxybutynin is about 0.7:1, and the sustained plasma concentrationsof (R)-oxybutynin are similar to the peak concentrations obtainedfollowing oral administration. This comparable exposure to thetherapeutically active (R)-oxybutynin moiety is consistent with theinvention.

Thus, with transdermal administration, it has been discovered that: themean AUC ratio of (R)—N-desethyloxybutynin to (R)-oxybutynin is lowered,resulting in greatly reduced amounts of the active metabolites ofoxybutynin, while providing a therapeutically effective amount ofoxybutynin.

By comparing FIGS. 4, 5, and 7, it becomes clear that the presentcompositions and methods provide an optimal ratio of plasmaconcentrations of metabolites, such as (R)—N-desethyloxybutynin, tooxybutynin, such that these methods and compositions minimize adverseexperiences associated with oxybutynin administration, as compared totraditional oral formulations, while maintaining therapeuticallysufficient concentrations of (R)-oxybutynin to provide the benefits ofoxybutynin therapy. As indicated above, these compositions and methodsoffer a significant advancement in oxybutynin therapy.

3) Therapeutic Aspects

A clinical study on the efficacy and minimization of incidence andseverity of adverse drug experiences associated with non-orallyadministered oxybutynin was conducted using 72 human subjects (patients)with overactive bladder. Approximately one-half of the patients wereadministered oxybutynin hydrochloride in an oral dosage formulation. Theremaining patients were administered oxybutynin using a non-oral routeof delivery such as a transdermal adhesive matrix patch over a period ofabout 6 weeks. The results are displayed graphically in FIGS. 4 and 5.

The non-oral, sustained-release composition of this invention wascompared for its therapeutic efficacy with the conventional 5 mg oraltablet of oxybutynin. The mean number of incontinent episodesexperienced per day as derived from a multiple-day patient urinary diarywas used as the desired therapeutic efficacy indicator. The data showthat the number of incontinent episodes for those individuals treated bythe non-oral method of the present invention is nearly identical to thenumber for those treated with the oral formulation. (See FIG. 4).

Next, the non-oral sustained-release formulation of the presentinvention was compared to the conventional immediate-release oral tabletfor the incidence and severity of adverse drug experiences. The adverseexperience of dry mouth was selected as an indicator for thisexperiment. As can be seen, only 6% of the participants who received theconventional oral oxybutynin tablet reported no dry mouth effects.Conversely, 94% of these participants reported experiencing some drymouth.

In contrast, 62% of the participants who were treated with thetransdermal adhesive matrix patch of the present invention reported nodry mouth effects. Therefore, only 38% of these participants reportedexperiencing some dry mouth, and none rated the dry mouth asintolerable.

These data show that the adverse experiences associated with oxybutyninadministration can be minimized significantly, while fully retaining thetherapeutic efficacy of oxybutynin by administering oxybutynin such thatan optimal ratio of AUC of oxybutynin metabolite to oxybutynin results.

4) Summary of Pharmacokinetic Aspects of the Invention

From the above-described pharmacokinetic data, the following aspects ofthe invention can be presented. In one aspect, the mean peak plasmaconcentration of an oxybutynin metabolite is less than about 8 ng/ml. Inanother aspect, the mean peak plasma concentration of the metabolite isfrom about 0.5 ng/ml to about 8 ng/ml; in yet another aspect, theconcentration is less than about 5 ng/ml; in yet another aspect, theconcentration is from about 1.0 ng/ml to about 3 ng/ml. In some aspects,the metabolite of oxybutynin is N-desethyloxybutynin.

In some aspects, the mean oxybutynin metabolite AUC is reduced to anamount which does not exceed the oxybutynin AUC by more than a ratio ofabout 2:1. In some aspects, the mean oxybutynin metabolite AUC isreduced to less than about 0.9:1 ng/ml.

In some aspects, the present invention provides compositions and methodsfor administering oxybutynin to a subject such that the mean AUC ratioof oxybutynin to an oxybutynin metabolite is about 0.5:1 to about 5:1.In some aspects, the ratio is from about 0.5:1 to about 4:1; in someother aspects, the ratio is from about 1:1 to 5:1; in yet other aspects,the ratio is from about 0.8:1 to about 2.5:1; in yet some other aspects,the ratio is from about 0.8:1 to about 1.5:1. In all the above aspects,the metabolite may be N-desethyloxybutynin.

Another way of characterizing the method of the present invention is byspecifying particular plasma concentrations for oxybutynin andmetabolite concentrations at certain time intervals following treatmentinitiation. Therefore, in one aspect, oxybutynin plasma concentrationsare below about 2.0 ng/ml at about 6 hours after oxybutynin treatmentinitiation. In another aspect, the metabolite plasma concentrations arealso below about 2.0 ng/ml at about 6 hours after treatment initiation.

In yet another aspect, oxybutynin and its metabolite plasmaconcentrations are below about 8 ng/ml at about 24 hours after initialoxybutynin administration. Further, mean steady state oxybutynin and itsmetabolite plasma-concentrations are below about 8 ng/ml for theduration of oxybutynin treatment.

In one aspect, the mean peak and mean AUC for (R)—N-desethyloxybutyninare about equal to or less than the mean peak, and mean AUC for(S)—N-desethyloxybutynin. In another aspect, the mean AUC ratio of(R)—N-desethyloxybutynin to (S)—N-desethyloxybutynin is about 0.9:1. Inyet another aspect, the mean peak and mean AUC for (R)-oxybutynin areapproximately equal to (R)—N-desethyloxybutynin. In another aspect, theratio of (R)—N-desethyloxybutynin to (S)—N-desethyloxybutynin is about1:1.

In an additional aspect, (R)—N-desethyloxybutynin has a mean peak plasmaconcentration of less than about 4 ng/mL. In another aspect,(R)—N-desethyloxybutynin has a mean peak plasma concentration betweenabout 0.25 to about 4 ng/ml, and about 1.5 ng/ml.

In a one aspect, (R)—N-desethyloxybutynin has a mean AUC of about 100ng×hr/ml. In another aspect, (R)—N-desethyloxybutynin has a mean AUCfrom about 30 ng×hr/ml to about 170 ng×hr/ml.

In yet another aspect, the plasma concentration of(R)—N-desethyloxybutynin is below about 1 ng/ml at about 6 hours afterinitiation of oxybutynin administration. In a further aspect, the plasmaconcentration of (R)—N-desethyloxybutynin is below about 2 ng/ml atabout 24 hours after initiation of oxybutynin administration.

Therapeutic oxybutynin plasma concentrations vary based on the severityof incontinence. Generally, therapeutic results may be obtained fromoxybutynin plasma concentrations as low as 0.5 ng/ml. Therapeutic bloodlevels may be achieved using the method of the present invention in aslittle as 3 hours after treatment initiation, with peak oxybutyninplasma concentrations being reached in about 24 hours. However, thesegeneral parameters are not limitations on the way in which the desiredplasma levels may be achieved. Different delivery methods, rates, andamounts may be used to effect the desired plasma concentrations byemploying a formulation which produces different parameters.

5) Composition Aspects

Any pharmaceutically acceptable compositions and methods foradministering such compositions may be used for achieving the desiredaspects of this invention. For example, oral and non-oral compositionsand methods of administration can be used. Non-oral compositions andmethods of administration include parenteral, implantation, inhalation,and transdermal compositions and methods.

Oral compositions and administrations can comprise of slow-releasecompositions that are designed to mimic the non-oral compositions andadministrations that are specifically disclosed herein in terms of theirpharmacokinetic attributes described above. One of ordinary skill in theart would readily understand how to formulate and administer suchslow-release oral formulations. These formulations can take the form ofa tablet, capsule, caplet, pellets, encapsulated pellets, etc., or aliquid formulation such as a solution or suspension. See, for example,U.S. Pat. No. 5,840,754, and WO 99/48494 which are incorporated byreference in their entirety.

Parenteral compositions and administrations may include intravenous,intra-arterial, intramuscular, intrathecal, subcutaneous, etc. Thesecompositions can be prepared and administered to provide slow-release ofoxybutynin to achieve the pharmacokinetic profile and therapeuticbenefits described above. One specific example of preparing adepot-formulation for parenteral use is provided herein. General methodsfor preparing sustained delivery of drugs for parenteral use comprisingmicrospheres are known in the art. See for example, U.S. Pat. Nos.5,575,987, 5,759,583, 5,028,430, 4,959,217, and 4,652,441, which areincorporated by reference in their entirety.

Implantation is a technique that is well-established to providecontrolled release of drugs over a long period of time. Severalsubcutaneously implantable devices have been disclosed in the art. Seefor example, U.S. Pat. Nos. 5,985,305, 5,972,369, and 5,922,342, whichare incorporated by reference in their entirety. By employing thesegeneral techniques, one of ordinary skill in the art can prepare andadminister implantable oxybutynin compositions to achieve thepharmacokinetic and therapeutic benefits of this invention.

Examples of oxybutynin transdermal administration formulations includebut are not limited to: 1) topical formulations such as ointments,lotions, gels, pastes, mousses, aerosols, and skin creams; 2)transdermal patches such as adhesive matrix patches and liquid reservoirsystems. Other non-oral examples include transmucosal tablets such asbuccal, or sublingual tablets or lozenges, and suppositories.

In addition to the desired amount of oxybutynin, transdermal oxybutyninformulations may also include a permeation enhancer, or mixture ofpermeation enhancers in order to increase the permeability of the skinto oxybutynin. An index of permeation enhancers is disclosed by David W.Osborne and Jill J. Henke, in their publication entitled SkinPenetration Enhancers Cited in the Technical Literature, published in“Pharmaceutical Technology” (June 1998), which may also be found at theworldwide web address known as:pharmtech.com/technical/osborne/osbome.htm, which is incorporated byreference herein.

More particularly, permeation enhancers known to enhance the delivery ofoxybutynin include but are not limited to: fatty acids, fatty acidesters, fatty alcohols, fatty acid esters of lactic acid or glycolicacid, glycerol tri-, di- and monoesters, triacetin, short chainalcohols, and mixtures thereof. Specific species or combinations ofspecies may be selected from the above listed classes of compounds byone skilled in the art, in order to optimize enhancement of theparticular oxybutynin composition employed.

The transdermal formulation of the present invention may take the formof a non-occlusive topical formulation, such as a gel, ointment such asa lotion, cream or paste, or an occlusive device such as a transdermalpatch. A transdermal patch in accordance with the present invention mayeither be an adhesive matrix patch, a liquid reservoir system typepatch, a buccal tablet, or the like. Optional ingredients such asadhesives, excipients, backing films, etc, and the required amount ofeach will vary greatly depending upon the type of patch desired, and maybe determined as needed by one ordinarily skilled in the art. Methodsfor preparing and administering the transdermal formulations with theabove-described characteristics are known in the art. See, for example,U.S. Pat. Nos. 5,762,953, and 5,152,997, which are incorporated byreference in their entirety.

In one aspect of the present invention, a free form oxybutynin ointmentmay be prepared for topical administration in accordance with thediscussion herein. An ointment is a semisolid pharmaceutical preparationbased on a well known materials such as an oleaginous base, lanolin,emulsions, or water-soluble bases. Preparation of ointments is wellknown in the art such as described in Remington, supra, vol. 2, pp.1585-1591. Such preparations often contain petrolatum or zinc oxidetogether with an active agent. Oleaginous ointment bases suitable foruse in the present invention include generally, but are not limited to,vegetable oils, animal fats, and semisolid hydrocarbons obtained frompetroleum. Absorbent ointment bases of the present invention may containlittle or no water and may include components such as, but not limitedto, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases of the present invention are eitherwater-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and mayinclude, but are not limited to, cetyl alcohol, glyceryl monostearate,lanolin, polyalkylsiloxanes, and stearic acid. Water-soluble ointmentbases suitable for use in the present invention may be prepared frompolyethylene glycols of varying molecular weight.

In an additional aspect, ointments of the present invention may includeadditional components such as, but not limited to, additional activeagents, excipients, solvents, emulsifiers, chelating agents,surfactants, emollients, permeation enhancers, preservatives,antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes.The specific choice and compositions of such additional components maybe made by those skilled in the art in accordance with the principles ofthe present invention.

In another aspect of the present invention, a free form oxybutynin creammay be prepared in accordance with the principles of the presentinvention. Creams are a type of ointment which are viscous liquids orsemisolid emulsions, either oil-in-water or water-in-oil, as is wellknown in the art. Cream bases may be soluble in water, and contain anoil phase, an emulsifier, an aqueous phase, and the active agent. In adetailed aspect of the present invention, the oil phase may be comprisedof petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. Inanother detailed aspect of the present invention, the aqueous phase mayexceed the oil phase in volume, and may contain a humectant. In anotherdetailed aspect of the present invention, the emulsifier in a creamformulation may be a nonionic, anionic, cationic or amphotericsurfactant.

In a more detailed aspect of the present invention, the free formoxybutynin cream is an oil-in-water emulsion. The water phase of theoxybutynin cream may contain between about 20 and about 60% w/w ofwater, between about 1 and about 15% w/w of at least one emulsifier, upto about 50% w/w of an oil phase, and up to about 1% w/w of apreservative such as a paraben. The oil phase of the free formoxybutynin cream may contain up to about 40% w/w of a solvent, up toabout 15% w/w of at least one emulsifier, up to about 40% w/w of an oilphase, and up to about 1% w/w of a preservative such as a paraben.

In another aspect of the present invention, a free form oxybutyninlotion may be prepared in accordance with the principles of the presentinvention. A lotion is an ointment which may be a liquid or semi-liquidpreparation in which solid particles, including the active agent, arepresent in a water or alcohol base. Lotions suitable for use in thepresent invention may be a suspension of solids or may be anoil-in-water emulsion. In another aspect of the present invention,lotions may also contain suspending agents which improve dispersions orother compounds which improve contact of the active agent with the skin,e.g., methylcellulose, sodium carboxymethylcellulose, or similarcompounds.

In an additional aspect, oxybutynin lotions of the present invention mayinclude additional components such as, but not limited to, additionalactive agents, excipients, solvents, emulsifiers, chelating agents,surfactants, emollients, permeation enhancers, preservatives,antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes.The specific choice and compositions of such additional components maybe made by those skilled in the art in accordance with the principles ofthe present invention and may differ from the components which would bechosen for other topical formulations of the present invention.

In another more detailed aspect of the present invention, free formoxybutynin lotions may be an emulsion of a water and oil phase. Thewater phase of the oxybutynin lotion may contain between about 20% w/wand about 90% w/w of an excipient such as water, up to about 5% w/w of asurfactant, up to about 5% w/w of sodium chloride or the like, and up toabout 1% w/w of a preservative such as a paraben. The oil phase of theoxybutynin lotion may contain up to about 40% w/w of at least onesolvent such as glycerin and cetyl alcohol, up to about 10% w/w of anabsorbent base such as petrolatum, up to about 5% w/w of an antioxidantsuch as isopropyl palmitate, up to about 5% w/w of an oil phase such asdimethicone, and up to about 1% w/w of a preservative such as a paraben.

In yet another aspect of the present invention, a free form oxybutyninpaste may be prepared in accordance with the present invention. Pastesof the present invention are ointments in which there are significantamounts of solids which form a semisolid formulation in which the activeagent is suspended in a suitable base. In a detailed aspect of thepresent invention, pastes may be formed of bases to produce fatty pastesor made from a single-phase aqueous gel. Fatty pastes suitable for usein the present invention may be formed of a base such as petrolatum,hydrophilic petrolatum or the like. Pastes made from single-phaseaqueous gels suitable for use in the present invention may incorporatecellulose based polymers such as carboxymethylcellulose or the like as abase.

In an additional aspect, oxybutynin pastes of the present invention mayinclude additional components such as, but not limited to, additionalactive agents, excipients, solvents, emulsifiers, chelating agents,surfactants, emollients, permeation enhancers, preservatives,antioxidants, lubricants, pH adjusters, adjuvants, dyes, and perfumes.

In another aspect of the present invention, a free form oxybutynin gelmay be prepared. An oxybutynin gel prepared in accordance with thepresent invention may be a preparation of a colloid in which a dispersephase has combined with a continuous phase to produce a viscous product.The gelling agent may form submicroscopic crystalline particle groupsthat retain the solvent in the interstices. As will be appreciated bythose working in art, gels are semisolid, suspension-type systems.Single-phase gels can contain organic macromolecules distributedsubstantially uniformly throughout a carrier liquid, which may beaqueous or non-aqueous and may contain an alcohol or oil.

In another aspect, the transdermal formulation of the present inventionmay be a topical gel containing oxybutynin for unoccluded administrationto the skin. A variety of specific gel vehicles are known to those ofordinary skill in the art. Examples of specific gel types, theirmanufacture and use may be found, for example, in U.S. Pat. Nos.2,909,462; 4,340,706; 4,652,441; 5,516,808; 5,643,584; 5,840,338;5,912,009; and 6,258,830, each of which are incorporated herein byreference in their entirety.

However, in some aspects, the gel formulation may be prepared byproviding a gelling agent, usually in a powdered form, and adding anexcipient such as water in the case of a hydrophilic gelling agent ormineral oil in the case of a hydrophobic gelling agent. The gel thenswells and may be optionally neutralized. In a separate vessel,oxybutynin may be dissolved in an appropriate solvent. The dissolvedoxybutynin and the gel may then be mixed to form the final gelformulation. Other methods of producing a drug-containing gel will berecognized by those of ordinary skill in the art.

Although gels used in reservoir devices may have similar componentsadditional considerations may be important in designing a free form gel.For example, free form gels may offer a number of advantages, such asease of administration, increased patient compliance, simple adjustmentof dosage, decreased manufacturing costs, and reduced skin irritation.Moreover, certain excipients useful in effecting administration ofoxybutynin may be included in a free form gel in greater amounts, thanis possible in an occluded gel, such as in an LRS patch, due toperformance factors such as skin irritation, etc.

In accordance with a more detailed aspect of the present invention, thefree form gel may include a variety of additional components such as,but not limited to, additional active agents, excipients, solvents,emulsifiers, chelating agents, surfactants, emollients, permeationenhancers, preservatives, antioxidants, lubricants, pH adjusters,adjuvants, dyes, and perfumes. The additional components may be added tothe dissolved oxybutynin either before or after combination with thegel. Further, in order to prepare a uniform gel, dispersing agents suchas alcohol or glycerin can be added, or the gelling agent can bedispersed by trituration, mechanical mixing or stirring, or combinationsthereof. It will be recognized, however, by those skilled in the artthat other methods and means of incorporating the oxybutynin and othercomponents into the gel may be employed consistent with the teachings ofthe present invention.

In accordance with the present invention, the free form gel may beaqueous or non-aqueous based. In either case, the formulation should bedesigned to deliver the oxybutynin in accordance with the release ratesand blood plasma concentrations recited herein. In one aspect of thepresent invention, aqueous gels may comprise water or water/ethanol andabout 1-5 wt % of a gelling agent. In another aspect of the presentinvention, non-aqueous gels may be comprised of silicone fluid, such ascolloidal silicon dioxide, or mineral oil. The suitability of aparticular gel depends upon the compatibility of its constituents withboth the oxybutynin and the permeation enhancer, if used, and any othercomponents in the formulation.

In accordance with the present invention, oxybutynin used in the freeform gel may be provided as the oxybutynin free base, its acid additionsalts such as oxybutynin HCl, their analogs and related compounds,isomers, polymorphs, prodrugs, optically pure (R) or (S) isomers,racemic mixture and combinations thereof. The oxybutynin may be providedin a micronized form or other powdered form. In one aspect of thepresent invention, the oxybutynin is present at about 0.1 wt % to about10 wt % of the free form gel. In accordance with one aspect of thepresent invention, the oxybutynin may be present between about 5 andabout 20 mg/gram.

In accordance with the present invention, the gelling agent may be acompound of high molecular weight which acts as a thickening agent toproduce a semisolid or suspension-type formulation. As mentioned above,gelling agents may be hydrophobic or hydrophilic and are generallypolymers. Gels which incorporate hydrophilic polymers are referred to ashydrogels, as is understood by those skilled in the art.

Examples of suitable gelling agents for use in the present invention mayinclude synthetic polymers such as, but not limited to, polyacrylicacids or poly(l-carboxyethylene), carboxypolymethylenes prepared fromacrylic acid cross-linked with allyl ethers of (polyalkyl) sucrose orpentaerythritol (e.g. CARBOPOL 940/941/980/981/1342/1382 and carbamerpolymers such as carbomer 934P/974P), sodium acrylate polymers (e.g.AQUAKEEP J-550/J-400), other polycarboxylic acids, alkyl acrylatepolymers (e.g. PEMULEN), and mixtures or copolymers thereof. In anotheraspect of the present invention, the gelling agent is a CARBOPOL. In onemore detailed aspect of the present invention, the gelling agent is analkyl acrylate polymer. In yet another aspect of the present invention,the gelling agent is a mixture of CARBOPOL and an alkyl acrylatepolymer.

In another aspect of the present invention, suitable gelling agents mayinclude vinyl polymers such as but not limited to carboxyvinyl polymers,polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl methyl ether,polyvinyl ether, polyvinyl sulfonates, and mixtures or copolymersthereof.

In a further aspect of the present invention, suitable gelling agentsmay include polymers such as but not limited to polyethylene compounds(e.g. polyethylene glycol, etc.), polysaccharides (e.g. polysucrose,polyglucose, polylactose, etc.) and salts thereof, acrylic acid esters,alkoxybutyninpolymers (e.g. polyoxyethylene-polyoxypropylene copolymerssuch as the PLURONIC line of BASF, Parsippany, N.J.), polyethylene oxidepolymers, polyethers, gelatin succinate, colloidal magnesium aluminumsilicate (which may be useful as a gel stabilizer in conjunction withanother gelling agent), petroleum jelly and mixtures of copolymersthereof.

Suitable gelling agents also include cellulose polymers such ashydroxypropyl cellulose (e.g. KLUCEL), hydroxypropylmethyl cellulose(e.g. KLUCEL HF, METHOCEL), hydroxypropylethyl cellulose,hydroxypropylbutyl cellulose, hydroxypropylpentyl cellulose,hydroxyethyl cellulose (NATROSOL), ethylcellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose phthalate, and celluloseacetate. In one more detailed aspect of the present invention, thegelling agent is hydroxypropyl cellulose. In a more detailed aspect ofthe present invention, the gelling agent is hydroxyethyl cellulose. Inyet another aspect of the present invention, the gelling agent is amixture of hydroxyethyl cellulose and an alkyl acrylate polymer. In afurther aspect of the present invention, the gelling agent is a mixtureof hydroxypropyl cellulose and a CARBOPOL.

In yet another more detailed aspect of the present invention, suitablegelling agents may be natural gelling agents include, dextran, gaur-gum,tragacanth, xanthan gum, sodium alginate, sodium pectinate, sodiumalginate, acacia gum, Irish moss, karaya gum, guaiac gum, locust beangum, etc., while natural high molecular weight compounds include, amongothers, various proteins such as casein, gelatin, collagen, albumin(e.g. human serum albumin), globulin, fibrin, etc. and variouscarbohydrates such as cellulose, dextrin, pectin, starches, agar,mannan, and the like. These substances may be also be chemicallymodified, e.g. esterified or etherified forms, hydrolyzed forms (e.g.sodium alginate, sodium pectinate, etc.) or salts thereof.

The amount of gelling agent employed in a gel of the present inventionmay vary depending on the specific result to be achieved. However, inone aspect, the amount of gelling agent may be from about 0.05 to about10 wt % of the gel formulation. In a more detailed aspect, the amount ofgelling agent may be 0.1 to 5 wt % of the gel formulation prior tointroduction of the dissolved oxybutynin and any accompanyingcomponents. In yet a more detailed aspect, the free form gel may containabout 0.1 to about 3 wt % of a gelling agent in the gel formulation.

In another aspect of the present invention, solvents or solubilizingagents may also be used in the free form gel. Such solvents may benecessary when the drug is not soluble in the chosen gelling agent.Suitable solvents for use in the present invention include, but are notlimited to lower alcohols, ethanol, isopropanol, benzyl alcohol,propanol, methanol, other C₄-C₁₀ mono-alcohols and mixtures thereof. Inanother aspect the solvents suitable for use in the present inventionmay include albumin, gelatin, citric acid, ethylenediamine sodiumtetraacetate, dextrin, DMSO, dimethylformamide, 2-pyrrolidone,N-(2-hydroxyethyl) pyrrolidone, N-methyl pyrrolidone,1-dodecylazacycloheptan-2-one and othern-substituted-alkyl-azacycloalkyl-2-ones (azones), sodium hydrosulfiteand mixtures thereof.

In one aspect, the ethanol may be present from about 60% to about 85%w/w of the formulation. In another aspect, the ethanol may be presentfrom about 65% to about 80% w/w of the formulation. In another aspect,the ethanol may be present from about 70% to about 85% w/w of theformulation. In another aspect, the ethanol may be present from about70% to about 75% w/w of the formulation.

In one aspect, the water may be present from about 1% to about 30% w/wof the formulation. In another aspect, the water may be present fromabout 5% to about 30% w/w of the formulation. In another aspect, thewater may be present from about 5% to about 20% w/w of the formulation.In yet another aspect, the water may be present from about 10% to about30% w/w of the formulation. In another aspect, the water may be presentfrom about 10 to about 25% w/w of the formulation. In yet anotheraspect, the water may be present from about 10% to about 20% w/w of theformulation. In yet another aspect, the water may be present from about15% to about 25% w/w of the formulation. In another aspect, the watermay be present from about 20% to about 25% w/w of the formulation.

Those of ordinary skill in the art will appreciate that the specificamount and type of solvent selected may be determined based on aspecific result to be achieved. However, in one aspect, the amount ofsolvent may be at least about 25% w/w of the formulation. In anotheraspect, the amount of solvent may be at least about 30% w/w of theformulation. In a further aspect, the amount of solvent may be at leastabout 40% w/w of the formulation. In an additional aspect, the amount ofsolvent may be at least about 70% w/w of the formulation.

In yet a more detailed aspect of the present invention, excipients suchas, but not limited to, water, mineral oils, or silicon fluids may alsobe added and are largely dependent on the chosen gelling agent. Theexcipient may comprise a substantial portion of the gel formulation,i.e. greater than about 50%. In one aspect of the present invention, thefree form gel contains excipient in an amount from 0% to about 75%

In yet another more detailed aspect of the present invention, anemulsifier may also be used particularly when solvent is used.Emulsifiers suitable for use in the present invention include, but arenot limited to, polyols and esters thereof such as glycols, propyleneglycol, polyethylene glycol, glycolhexylene glycol, ethylene glycol,glycerol, butanediol, polyethylene glycol monolaurate, and propyleneglycol ester of alginic acid. Emulsification may be accomplished byconventional dispersion techniques. For example, intermittent shaking,mixing by means of a propeller mixer, turbine mixer or the like, colloidmill operation, mechanical homogenization, ultrasonication, or otherknown methods may be utilized. Emulsifiers may form stable oil-in-wateremulsion, and such emulsifiers are exemplified by anionic surfactants(e.g. sodium oleate, sodium stearate, sodium laurylsulfate, etc.),nonionic surfactants (e.g. polyoxyethylene sorbitan fatty acid esters(Tween 80 and Tween 60, Atlas Powder, U.S.A.), polyoxyethylene castoroil derivatives (HCO-60 and HCO-50, Nikko Chemicals, Japan], etc.),polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethylcellulose,lecithin, gelatin, and combinations thereof. The concentration of theemulsifier may be selected from the range of about 0.01% to about 20%.It will be noted that many of these emulsifiers also act as gellingagents.

In another aspect of the present invention, a chelating agent may beused to prevent precipitation or decomposition of the oxybutynin.Suitable chelating agents for use in the present invention may include,but are not limited to, sodium and calcium salts of EDTA, and edetatedisodium.

In yet a more detailed aspect of the present invention, surfactants maybe desirable since the inclusion of a surfactant may have the dualbenefit of helping to maintain the active ingredient in uniformsuspension in the gel formulation, while enhancing the bio-availabilityof the oxybutynin. Further, many surfactants also act as permeationenhancers. Surfactants suitable for use in the present invention mayinclude, but are not limited to, lecithin; sorbitan monoesters, such assorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monostearate; polysorbates, such as those prepared from lauric,palmitic, stearic and oleic acids (polysorbate 20 and polysorbate 40);mononylphenyl ethers of polyethylene glycols, such as the monoxynols(e.g. octoxynol and nonoxynol); polyoxyethylene monoesters, such aspolyoxeethylene monostearate, polyoxyethylene monolaurate,polyoxyethylene monoleate; dioctyl sodium sulfosuccinate; sodium laurylsulfate, sodium laurylate, sodium laurate, polyoxyethylene-sorbitanmonolaurate; and polyoximers having a molecular weight between 2,000 and8,000, poloxamer (182, 184, 231, 407); and mixtures thereof

In another aspect of the present invention, additional suitable solventsfor use in the present invention may include, but are not limited to,ethanol, glycerin, triethanolamine; ureas such as diazolidinyl urea;anionic, cationic, amphoteric and nonionic surfactants, includingdialkyl sodium sulfosuccinate, polyoxyethylene glycerol, polyethyleneglycol glyceryl stearate, polyoxyethylene stearyl ether,propoxy-ethoxybutynincopolymer, polyoxyethylene fatty alcohol ester,polyoxyethylene fatty acid ester, glycol salicylate, crotamiton,ethoxylated hydrogenated castor oil, butoxylated hydrogenated castoroil, limonene, peppermint oil, eucalyptus oil, cetyltrimethylammoniumbromide, benzalkonium chloride, and Tween (20, 40, 60, 80). In oneaspect of the present invention, a non-ionic surfactant may be used ifthe stability of oxidizable ingredients in the free form gel is affectedby the ionic strength of the formulation. In one aspect of the presentinvention, ethanol is used as the solvent. In another aspect of thepresent invention, glycerin is used as the solvent. In another aspect ofthe present invention, the solvent or surfactant may be present in anamount from about 30 wt % to about 100% of the free form gel. Thesurfactant or solvent may be present in an amount up to about 30% byweight of the free form gel.

In another aspect of the present invention, the free form gel maycontain up to about 10 wt % of a lipophilic or hydrophobic agent, whichmay serve as an emollient or anti-irritant, as an additional help inrelieving irritation, if any, caused by the oxybutynin or otherformulation components. Emollients suitable for use in the presentinvention may include lipophilic agents such as, but not limited to,fatty materials such as fatty alcohols of about 12 to 20 carbon atoms,fatty acid esters having about 12 to 20 carbon atoms in the fatty acidmoiety, petrolatum, mineral oils, and plant oils such as soybean oil,sesame oil, almond oil, aloe vera gel, glycerol, and allantoin. Inanother aspect of the present invention glycerol is used as theemollient.

In yet another detailed aspect of the present invention, other additivesmay be used in order to adjust the pH of the free form gel and thusreduce irritation and/or aid in obtaining proper gelling, pH additivesmay be required such as, but not limited to, organic amines (e.g.methylamine, ethylamine, di/trialkylamines, alkanolamines,dialkanolamines, triethanolamine), carbonic acid, acetic acid, oxalicacid, citric acid, tartaric acid, succinic acid or phosphoric acid,sodium or potassium salts thereof, hydrochloric acid, sodium hydroxide,ammonium hydroxide and mixtures thereof.

Surprisingly, it has been discovered that in some embodiments, thespecific pH of the formulation may enhance the permeation of oxybutyninthrough the skin as compared to another pH. As a result, in one aspectof the present invention, the oxybutynin gel formulation may have a pHthat enhances oxybutynin penetration through the skin as compared to thepenetration obtained at a different pH. In some aspects, the pH thataids in penetration enhancement may be a pH which is higher than a pHthat does not aid in penetration enhancement. In some aspects, the pHmay be a basic pH. In other aspects, the pH may be a near neutral pH. Inan additional aspect, the pH may be a pH substantially equivalent to theinherent pH of the specific type of oxybutynin used. In another aspect,the specific pH may provide a permeation enhancement that is at leastabout 20% greater than the enhancement obtained at a different pH.Examples of specific formulations and pH therefore that enhanceoxybutynin permeation are contained below.

In yet another detailed aspect of the present invention, permeationenhancers may also be added to increase the rate of permeation of theactive agent, such as oxybutynin, across the epidermal layer. Usefulpermeation enhancers allow desired drug delivery rates to be achievedover a reasonably sized skin area, are non-toxic, cause minimalirritation, and are non-sensitizing. Although some of the solventsmentioned above also act as permation enhancers other enhancers suitablefor use in the present invention include, but are not limited to,triacetin, monoglycerides, glycerol monooleate, glycerol monolaurate,glycerol monolineoleate, glycerol dioleate, glycerol trioleate; fattyacid esters such as isopropyl myristate, isopropyl adipate,methylpropionate and ethyl oleate; thioglycerol, calcium thioglycolate,lauric acid, myristic acid, strearic acid, oleic acid, oleyl alcohol,linoleic acid, palmitic acid, valeric acid, isopropanol, isobutanol, andmixtures thereof. In one aspect of the present invention, the enhanceris a monoglyceride. In another aspect of the present invention theenhancer is triacetin.

Additional enhancers suitable for use in the present invention mayinclude, but are not limited to, N-methylpyrrolidone, N-dodecylpyrrolidone, hydroxypropyl-beta-cyclodextrin, lauryl alcohol, sulfoxidessuch as dimethylsulfoxide and decylmethylsulfoxide; ethers such asdiethylene glycol monoethyl ether and diethylene glycol monomethylether; 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (see for example, U.S. Pat. Nos.3,989,816, 4,316,893, 4,405,616 and 4,557,934, each of which isincorporated herein by reference); alcohols such as ethanol, propanol,octanol, benzyl alcohol, and the like; amides and other nitrogenouscompounds such as urea, dimethylacetamide, dimethylformamide,2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; organic acids, such as salicylicacid and salicylates, citric acid and succinic acid; certain peptides,e.g., peptides having Pro-Leu at the N-terminus and followed by aprotective group (see for example, U.S. Pat. No. 5,534,496 which isincorporated herein by reference); and mixtures thereof.

In another aspect, the free form gels of the present invention mayfurther contain about 0.05 to 2 weight % of a preservative,anti-microbial or anti-bacterial agent which prevents bacterial ormicrobial growth in the gel formulation. Preservatives suitable for usein the present invention may include, but are not limited to, sorbitol,p-oxybenzoic acid esters (e.g. methyl paraben, ethyl paraben, propylparaben, etc.), benzyl alcohol, chlorobutanol, betahydroxytoluene, andthimerosal. However, other conventional preservatives commonly used inpharmaceutical compositions will be readily recognized by those skilledin the art. In one aspect of the present invention, the preservative isa paraben.

In yet another aspect of the present invention, the free form gels mayinclude an antioxidant. Suitable antioxidants for use in the presentinvention may include, but are not limited to, dl-alpha-tocopherol,d-alpha-tocopherol, d-alpha-tocopherol acetate, d-alpha-tocopherol acidsuccinate, dl-alpha-tocopherol acid succinate, dl-alpha-tocopherolpalmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), butylatedhydroxyquinone, ethyl gallate, propyl gallate, octylgallate, lauryl gallate, cephalm, ascorbic acid, ascorbyl oleate,ascorbyl palmitate, sodium ascorbate, calcium ascorbate, hydroxycomarin,propylhydroxybenzoate, trihydroxybutylrophenone, dimethylphenol,diterlbulylphenol, vitamin E, lecithin and ethanolamine for example. Inone aspect of the present invention, the antioxidant contains atocopherol group. Other suitable antioxidants for oxybutynin will bereadily recognized by those skilled in the art.

In still another aspect of the present invention, lubricants may beadded to the free form gels of the present invention. Typical lubricantsinclude magnesium stearate, calcium stearate, zinc stearate, magnesiumoleate, magnesium palmitate, calcium palmitate, sodium suberate,potassium laurate, corn starch, potato starch, bentonite, citrus pulp,stearic acid, oleic acid, and palmitic acid.

In another aspect of the present invention, the topical formulationsdescribed herein may also be prepared with liposomes, micelles, ormicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer. Liposomal preparations for use in thepresent invention include cationic, anionic and neutral preparations.Cationic liposomes suitable for use in the present invention mayinclude, but are not limited to,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (LIPOFECTIN).Similarly, anionic and neutral liposomes may be used such asphosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline, dioleoylphosphatidyl glycerol, anddioleoylphoshatidyl ethanolamine. Methods for making liposomes usingthese and other materials are well known in the art.

In another detailed aspect of the present invention, micelles may beprepared to deliver oxybutynin in accordance with the method of thepresent invention. Micelles suitable for use in the present invention,are comprised of surfactant molecules arranged such that the polar endsform an outer spherical shell, while the hydrophobic, hydrocarbon chainends are oriented towards the center of the sphere, forming a core.Surfactants useful for forming micelles for use in the present inventioninclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethyl-ammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride,polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 andnonoxynol 30. Other methods for the preparation of micelles is known tothose skilled in the art.

In yet another aspect of the present invention, microspheres may also beincorporated into the present invention and encapsulate the oxybutyninand/or other components. Microspheres may be formed from lipids, such asphospholipids and preparation of microspheres generally is well known inthe art.

Finally, in another aspect of the present invention, the vehicles andformulations of the present invention may optionally contain minoramounts of such other commonly used cosmetic adjuvants or otheradditives such as dyes, perfumes, pacifiers, sunscreens, etc., as willbe readily recognized by those skilled in the art. In addition, it isalso contemplated that the free form gels of the present invention mayalso contain other components such as vitamins, lipids, hormones,additional active agents, or anti-inflammatory agents, such ascorticosteroids.

As will be appreciated by those skilled in the art, each specific typeof formulation may affect the rate of delivery and present additionalvariables in designing the composition of such a formulation. Theaddition of various components may also effect the drug deliveryproperties of the final topical formulation. Each component of thedelivery system may have independent effects or effects which occur incombination with another component and may vary depending on theparticular topical formulation used.

Several of the various components listed may serve more than onepurpose. Thus, although listed in one category, certain compounds mayhave recognized beneficial properties characteristic of anothercategory. The above categorization is provided merely to addorganization and is not meant to be a definitive classification of thecompounds listed. However, these general parameters are not limitationson the way in which the desired plasma levels may be achieved. Differentdelivery methods, rates, and amounts may be used to affect the desiredplasma levels by employing a formulation which produces differentparameters.

EXAMPLES

The following examples of non-oral delivery formulations having avariety of oxybutynin containing compositions are provided to promote amore clear understanding of the possible combinations of the presentinvention, and are in no way meant as a limitation thereon. Materialsused in the present invention were obtained from specific sources whichare provided as follows. Where the materials are available from avariety of commercial sources, no specific source has been provided.Oxybutynin free base was obtained from Ceres Chemical Co. Inc., WhitePlains, N.Y. (USA). The enantiomers of oxybutynin and namely, the (R)-and (S)-isomers were obtained from Sepracor. Sepracor, Marlborough,Mass. (USA).

Example 1: Preparation of Oxybutynin Adhesive Matrix Patch

The non-oral oxybutynin delivery devices used in the clinical studyreferred to above were 13 and/or 39 cm² transdermal adhesive matrixpatches. A general method of preparing transdermal adhesive matrixpatches is described by U.S. Pat. Nos. 5,227,169, and 5,212,199, whichare incorporated by reference in their entirety. Following this generalmethod, the oxybutynin patches of this invention were prepared asfollows:

Oxybutynin free base, triacetin (Eastman Chemical Co., Kingsport, N.Y.)and 87-2888 acrylic copolymer adhesives (National Starch and ChemicalCo., Bridgewater, N.J.) were mixed into a homogenous solution and coatedat 6 mg/cm² (dried weight) onto a silicone treated polyester releaseliner (Rexham Release, Chicago, Ill.) using a two zonecoating/drying/laminating oven (Kraemer Koating, Lakewood, N.J.) toprovide a final oxybutynin adhesive matrix containing 15.4%, 9.0%, and75.6% by weight oxybutynin, triacetin and acrylic copolymer adhesive,respectively. A fifty micron thick polyethylene backing film (3M, St.Paul, Minn.) was subsequently laminated onto the dried adhesive surfaceof the oxybutynin containing adhesive matrix and the final laminatestructure was die cut to provide patches ranging in size from 13 cm² to39 cm² patches.

Example 2: Preparation of Oxybutynin Biodegradable Microsphere DepotInjection

Biodegradable microspheres for effecting a sustained-release depotinjection may be used to deliver oxybutynin in accordance with themethod of the present invention. Microspheres were prepared by thefollowing method:

12,000 molecular weight poly-d,l lactic acid (“PLA”, BirminghamPolymers, Birmingham, Ala.) was dissolved into methylene chloride at afinal concentration of 20% by weight. Oxybutynin free base was dissolvedinto the PLA solution at 4% by weight in the final solution. Awater-jacketed reaction vessel (temperature controlled at 5 degreesCelsius) equipped with a true-bore stirrer fitted with a Teflon turbineimpeller was charged with a de-ionized water containing 0.1% Tween 80.

The oxybutynin/PLA/methylene chloride solution was added drop wise intothe reaction vessel and stirred to dispense the organic polymer phasewithin the aqueous solution as fine particles. The resultant suspensionwas filtered and washed once with de-ionized water and finally dried ona roto-evaporator to removed methylene chloride. The resultantmicrospheres can be injected either intramuscularly or subcutaneously toprovide a prolonged systemic release of oxybutynin.

Example 3: Preparation of Topical Oxybutynin Formulation

Topically applied oxybutynin containing gel may be used to deliveroxybutynin in accordance with the method of the present invention. Ageneral method of preparing a topical gel is known in the art. Followingthis general method, a topical gel comprising oxybutynin was prepared asfollows:

95% ethanol (USP) was diluted with water (USP), glycerin (USP), andglycerol monooleate (Eastman Chemical, Kingsport N.Y.) to provide afinal solution at ethanol/water/glycerin/glycerol monooleate percentratios of 35/59/5/1, respectively. Oxybutynin free base was thendissolved into the above solution to a concentration of 10 mg/gram. Theresultant solution was then gelled with 1% hydroxypropyl cellulose(Aqualon, Wilmington, Del.) to provide a final oxybutynin gel. One totwo grams of the above gel is applied topically to approximately 200 cm²surface area on the chest, torso, and or arms to provide topicaladministration of oxybutynin.

Example 4: Clinical Study to the Determine the Pharmacokinetics ofOxybutynin, N-Desethyloxybutynin, and their Respective (R) and (S)Isomers Following Oral Administration of Racemic Oxybutynin inComparison to Transdermally Administered Racemic Oxybutynin

A clinical study in 16 healthy volunteers compared, in a cross-overfashion, the comparative plasma concentrations and pharmacokinetics ofoxybutynin, N-desethyloxybutynin, and their respective (R)- and(S)-enantiomeric components.

Healthy volunteers were recruited from the local population and includedmen and women ranging in age from 19 to 45 years. Following a pre-studyexamination to confirm a healthy condition in all volunteers, eachsubject participated in 2 study periods during which the testmedications, either a transdermal oxybutynin system applied for 4 daysor a single 5 mg oral immediate-release dose of oxybutynin, wereadministered. Blood samples were collected periodically throughout thestudy periods. Plasma was harvested from the samples according to astandard method. The quantities of (R) and (S) oxybutynin and (R) and(S) N-desethyloxybutynin were measured in the plasma samples through theapplication of a validated mass spectrometric method coupled with liquidchromatographic separation of the individual constituents. A PerkinElmer high performance liquid chromatographic pump was used inconjunction with a Chrom Tech AGP 150.2 chromatographic column. The massspectrometry instrument was an API 300 operated in MRM scan mode withelectrospray ionization. A linear response of the quantitation of theanalytes was confirmed with standard solutions and the performance ofthe assay was controlled using quality control samples analyzed inconjunction with the study samples. The range of linearity was 0.5 to 75ng/ml with linear correlation coefficients greater than 0.99 for allanalytes.

FIGS. 1, 2, 3, 6, and 7 show graphical displays of these data. In FIG.1, oxybutynin and N-desethyloxybutynin plasma concentrations are shownfollowing administration of the 5 mg immediate-release oral dosageoxybutynin hydrochloride tablets, Ditropan® Alza Corporation. Thesetablets were obtained commercially and can be obtained from variousgeneric manufacturers. Plasma concentration is indicated on the verticalaxis, and time is indicated on the horizontal axis. As can be seen, theplasma concentrations of N-desethyloxybutynin are significantly greaterthan oxybutynin plasma concentrations. The mean AUC ratio forN-desethyloxybutynin to oxybutynin is about 10:1.

FIG. 3 illustrates the plasma concentration profiles for oxybutynin andN-desethyloxybutynin during and following application of the transdermalsystem. As can be seen, the N-desethyloxybutynin plasma concentrationsfor the adhesive matrix patch embodiment, fall well within theparameters prescribed by the present invention. The mean AUC ratio forN-desethyloxybutynin to oxybutynin is about 0.9:1 and the mean plasmaconcentrations for N-desethyloxybutynin are less than about 2.5 ng/ml.

FIGS. 6 and 7 illustrate the plasma concentrations of the individualisomers of oxybutynin and N-desethyloxybutynin as measured during theclinical trial described above. As can be seen in FIG. 6, oraladministration of oxybutynin leads to relatively high concentrations of(R)—N-desethyloxybutynin. This active metabolite moiety is present inthe greatest concentration, and is several times the concentration ofboth (R) and (S) oxybutynin. The mean ratio of AUC of(R)—N-desethyloxybutynin to (R)-oxybutynin is about 17:1 and the meanAUC ratio of (R)—N-desethyloxybutynin to (S)—N-desethyloxybutynin isabout 1.5:1.

Following application of the transdermal oxybutynin system, the mean AUCratio of the active moieties, (R)—N-desethyloxybutynin to(R)-oxybutynin, is about 1:1, substantially lower than following oraladministration. Additionally, the mean AUC ratio of(R)—N-desethyloxybutynin to (S)—N-desethyloxybutynin is about 0.9:1,consistent with substantially lower metabolic first pass conversion ofthe active (R)-oxybutynin to (R)—N-desethyloxybutynin. The mean AUCratio of (R)- to (S)-oxybutynin is about 0.7:1, similar to that presentfollowing oral administration.

The lower overall amount of oxybutynin delivered during transdermaldelivery of oxybutynin was estimated based on the residual amount ofoxybutynin remaining in the transdermal system after the 4-dayapplication period subtracted from the amount determined in unusedtransdermal systems. The mean amount delivered over 4 days was about 12mg or an average of about 3 mg/day. The oral dose of oxybutyninadministered in the study was 5 mg, a dose that may be administeredevery 12 hours, or two times daily, during therapeutic use of theproduct. This allows a comparison of a dose of about 5 mg every 12 hoursfor oral treatment compared to about 1.5 mg every 12 hours fortransdermal treatment.

-   -   In summary, the pharmacokinetics of transdermal, non-oral,        oxybutynin administration illustrate the aspects of the        invention with regard to a sustained, slower rate of        administration of oxybutynin and a lower dose or overall amount        of oxybutynin administered.

Example 5: Comparative Analysis of Therapeutic Efficacy and Incidenceand Severity of Anticholinergic Side Effects, Primarily Dry Mouth ofConventional Oral Tablet Formulation and Transdermal Formulation of thePresent Invention

A clinical study of the efficacy and incidence of side effects wasconducted in 72 patients with overactive bladder. These patients wererecruited by independent clinical investigators located in variousregions of the U.S.A. Approximately half of the patients wereadministered oxybutynin hydrochloride in an immediate-release oraldosage formulation. The remaining patients were administered oxybutyninusing in each case one or more 13 cm² oxybutynin containing transdermaladhesive matrix patches. In each of these treatment groups, themedications were blinded by the concomitant administration of matchingplacebo forms of the treatments. In the case of active oral treatment,the patients applied placebo transdermal systems that contained allingredients of the active transdermal system with the exception of theactive drug oxybutynin. In like fashion, the active transdermaltreatment group received matching oral formulations without the activeoxybutynin constituent.

In this study, the patients included both men and women, with themajority being women with an average age of 63-64 years. All patientshad a history of urinary incontinence associated with overactive bladderand demonstrated a mean of at least 3 incontinent episodes per dayduring a washout period during which no medical therapy for incontinencewas used.

Therapeutic efficacy was based on the mean number of incontinentepisodes experienced per day as derived from a multiple-day patienturinary diary. The data are displayed graphically in FIG. 4.

As can be seen, the number of incontinent episodes for those individualstreated by the non-oral method of the present invention is nearlyidentical to the number for those treated with the oral formulation.This indicates clearly that the present methods and compositions providefor a therapeutically effective treatment for urinary incontinence andoveractive bladder that is comparable to the conventional oralformulation, such as a 5 mg oral oxybutynin tablet. Incidence and/orseverity of adverse drug experience was also compared between theconventional oral tablet formulation of oxybutynin administered as aboveand the transdermal formulation. Anticholinergic adverse experience,such as the incidence and severity of dry mouth, was used as anindicator of the adverse experience that can be associated with theadministration of either formulation and represents an anticholinergicside effect. The clinical study participants were asked to report thisexperience according to a standardized questionnaire. The data derivedfrom the questionnaire are displayed graphically in FIG. 5. Thepercentage of participants reporting dry mouth is indicated on thevertical axis, and the severity of the dry mouth is indicated on thehorizontal axis.

As can be seen, only 6% of the participants who received the oral formreported no dry mouth effects. Conversely, 94% of these participantsreported experiencing some dry mouth. By contrast, 62% of theparticipants who were treated with the 13 cm² transdermal adhesivematrix patches reported no dry mouth effects. Therefore, only 38% ofthese participants reported experiencing some dry mouth. Therefore, theclinical data shows that matrix patch embodiment of the method of thepresent invention, provides a treatment for overactive bladder whichachieves nearly identical therapeutic effectiveness as an oral form,while significantly minimizing the incidence and or severity of adverseexperiences associated with oxybutynin administration.

FIG. 7 shows that the (R)—N-desethyloxybutynin concentrations are lowerthan the (S)—N-desethyloxybutynin concentrations, and further, theconcentrations of (R)-oxybutynin increase slowly and are maintained atan approximately constant level throughout the patch application timeperiod. The reduced plasma concentrations of (R)—N-desethyloxybutyninappears to have contributed to the minimization of the incidence andseverity of adverse drug experiences such as dry mouth, while the plasmaconcentrations of (R)-oxybutynin retain the therapeutic effectiveness ofthe treatment, as shown by FIGS. 4 and 5.

Example 6: Preparation of Free Form Oxybutynin Gel

A topically applied oxybutynin containing gel may be used to deliveroxybutynin in accordance with the method of the present invention. Thegel of the present invention, and those described in Examples 9 through11, were made by weighing glycerin (or other humectants and emollients)into a 6 oz jar, then pre-weighed water was added, followed bypre-weighed 2N sodium hydroxide (for oxybutynin chloride gel) or 2Nhydrochloride (for oxybutynin free base gel). The sodium hydroxide orsodium hydrochloride may be present at from 0 wt % to about 5 wt % ofthe total free form gel. Pre-weighed ethanol was added into a 6 oz jar.The active ingredient (either oxybutynin free base or oxybutyninchloride) was weighed into a weighing dish on an analytical balance thentransferred into the 6 oz jar. After being tightly capped, the jar washand shaken until both the active ingredient and glycerin completelydissolved. Next, pre-weighed gelling agent was transferred into the jar(agglomeration of the gelling agent can be avoided by slow dispersion ofthe gelling agent particles into the jar). The actual weights of eachingredient was determined by the difference in the transfer containerweight. The jar was capped, wrapped with parafilm and put on a wristshaker overnight to completely dissolve the gelling agent.

Example 7: Experimental Methods and In Vitro Flux Study for Free FormOxybutynin Gel

In vitro skin flux studies of Examples 9 through 11 were conducted usingfull-thickness skin samples (approximately 500 μm) obtained from skinbanks. The full-thickness skin samples were stored at −5° C. untilexperiments were conducted. The gender, age, sex and anatomical siteinformation for each donor was recorded when available.

The method used to apply a thin film of gel to the surface of the skinwas adapted from Chia-Ming Chiang et al., Bioavailability assessment oftopical delivery systems: in vitro delivery of minoxidil fromprototypical semi-solid formulations, IJP, 49:109-114, 1989, which isincorporated herein by reference. The stratum corneum side of a piece ofskin was attached to one side of an adhesive-coated metal shim having acircular hole of 0.64 cm² cut in the center. The shim-membrane assemblywas placed on top of a flat glass surface, and approximately 15 μL of aformulation was dispensed into the central cavity. With a microscopeslide, the gel was spread across the surface of the skin, loading a doseof approximately 7 μL over the 0.64 cm² diffusional surface area. Theapplied dose was approximately 11 μL of gel per cm² diffusional surfacearea, which is typical for topical applications.

The gel-loaded shim-membrane assembly was clamped between the donor andreceiver compartments of a modified Franz diffusion cell with the dermalside facing the receiver solution. The receiver compartment was filledwith 0.02% (w/v) NaN₃ to maintain sink conditions on the receiver sidethroughout the duration of the experiment. The donor compartment wasunoccluded and open to the atmosphere. Cells were placed in a water bathheated with circulating water and calibrated to maintain the skinsurface temperature at (32±1)° C.

At predetermined time points, the entire contents of the receivercompartment was collected for quantifying the amount of drug, and thereceiver compartment refilled with fresh receptor medium, taking care toeliminate any air bubbles at the skin/solution interface. Each of thesamples were analyzed using high performance liquid chromatography(HPLC). The cumulative amount of drug permeated per unit area at anytime t (Qt, μg/cm²) was determined over a 24-hr period as follows:

${Qt} = {\sum\limits_{n = 0}^{t}\frac{C_{n}V}{A}}$

where, C_(n) is the concentration (μg/mL) of the drug in the receiversample at the corresponding sample time, V is the volume of fluid in thereceiver chamber, and A is the diffusional area of the cell (0.64 cm²).

For the studies of Examples 8 through 10, typically four replicates wereobtained per skin per system. A comparison of the means of the valuesobtained for a given system from each skin indicated differences inpermeation due to differences in skin.

Example 8: Topical Oxybutynin Free Base Gel Example 8.1

TABLE 1 Formulation^(a) Et/E/G/D Q_(t) (t = 24 hours) J_(ss) (% w/w)(μg/cm²/t)^(b) (μg/cm²/t)^(b) 84.5/10/1.5/4 29.20 ± 20.24 1.22 ± 0.8480.5/10/1.5/8 44.92 ± 18.12 1.87 ± 0.76 ^(a)Et = ethanol; E = enhancer =triacetin; G = gelling agent = KLUCEL; D = drug = oxybutynin free base^(b)Mean ± SD (n = 4 skin donors)

These results show that an increase in permeation rate may be achievedby increasing the concentration of oxybutynin in the formulation. Thus,in one aspect of the invention, a method of increasing the oxybutyninflux rate by increasing the concentration of oxybutynin in theformulation is provided.

Example 8.2

TABLE 2 Formulation^(a) Et/W/G/D Q_(t) (t = 24 hours) J_(ss) (% w/w)(μg/cm²/t)^(b) (μg/cm²/t)^(b) 94.5/0/1.5/4.0 14.04 ± 9.47  0.56 ± 0.3974.5/20/1.5/4.0 19.11 ± 17.40 0.80 ± 0.73 ^(a)Et = ethanol; W = water; G= gelling agent = KLUCEL; D = drug = oxybutynin free base ^(b)Mean ± SD(n = 4 skin donors)

These results show that acceptable flux rates can be achieved using bothaqueous and non-aqueous gel formulations. The results further show thatflux rates may be increased by using an aqueous formulation. Thus, amethod is provided for increasing the flux rate of an oxybutynin byincreasing the water concentration contained in an oxybutynin gelformulation. In one aspect, the amount of water can be increased byabout 1% w/w to about 30% w/w. In another aspect, the amount of watercan be increased by about 5% w/w to about 25% w/w. In yet anotheraspect, the amount of water can be increased by about 10% w/w to about20% w/w. In one detailed aspect, the oxybutynin in the formulation maybean oxybutynin free base.

Example 8.3

TABLE 3 Formulation^(a) Et/E/G/D Q_(t) (t = 24 hours) J_(ss) Enhancer (%w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) None 94.5/0/1.5/4.0 10.02 ± 5.38 0.42± 0.22 Triacetin 84.5/10.0/1.5/4.0 14.73 ± 6.70 0.61 ± 0.28 ^(a)Et =ethanol; E = enhancer; W = water; G = gelling agent = KLUCEL; D = drug =oxybutynin free base ^(b)Mean ± SD (n = 4 skin donors)

Example 8.4

TABLE 4 Formulation^(a) Et/W/G/D Q_(t) (t = 24 hours) J_(ss) pH of gel(% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 6.0 74.5/20.0/1.5/4.0 15.90 ± 4.160.66 ± 0.17 9.8 74.5/20.0/1.5/4.0 20.71 ± 3.42 0.86 ± 0.41 ^(a)Et =ethanol; W = water; G = gelling agent = KLUCEL; D = drug = oxybutyninfree base ^(b)Mean ± SD (n = 4 skin donors)

Thus, a method is provided for increasing oxybutynin flux rate byincreasing the pH of the formulation. In one aspect, the formulation isa gel formulation and the pH is increased from about 4 to about 11. Inanother aspect, the pH is increased from about 5 to about 11. In yetanother aspect, the pH is increased from about 6 to about 11. In anotheraspect, the pH is increased from about 4 to about 10. In yet anotheraspect, the pH is increased from about 5 to about 10. In another aspect,the pH is increased from about 6 to about 10. In yet another aspect, thepH is increased from about 6 to about 9. In one aspect, the pH of thegel formulation is about 6. In yet another aspect, the pH of the gelformulation is about 9. It should be understood that the oxybutynin ispresent in either as its free base form, or its pharmaceuticallyacceptable salt (e.g., HCl) or a mixture thereof. In another aspect, theoxybutynin may be present as its R- or its S-isomer or itspharmaceutically acceptable salt or a mixture thereof. Moreover, theformulation may be prepared with or without a permeation enhancer. Thus,in one aspect, a method of increasing the oxybutynin flux rate from atopical formulation of oxybutynin by increasing the pH of theformulation which is substantially free of a permeation enhancer. Inanother aspect, a method of increasing the oxybutynin flux rate from atopical formulation of oxybutynin by increasing the pH of theformulation which may include a permeation enhancer. When theformulation comprises a permeation enhancer, the formulation may providean increased flux rate compared to a formulation that comprises anincreased pH but substantially free of an enhancer. In some aspects, theflux rate may be increased by at least two-fold. In some other aspects,the flux rates may be increased by 2-3 times, or even higher. In yetsome other aspects, the flux rate may be increased by 5-10 fold. Itshould also be understood that the increased flux rates due to increasedpH could be achieved with other topical formulations, such as creams,ointments, lotions, foams, sprays, and transdermal patches, and notnecessarily limited to the gel formulations.

Example 8.5

TABLE 5 Formulation^(a) Et/W/Gl/G/D Q_(t) (t = 24 hours) J_(ss) (% w/w)(μg/cm²/t)^(b) (μg/cm²/t)^(b) 74.0/20.0/0/2.0/4.0 13.26 ± 10.89 0.55 ±0.45 74.0/19.0/1.0/2.0/4.0 11.68 ± 10.63 0.49 ± 0.44 ^(a)Et = ethanol; W= water; Gl = glycerin; G = gelling agent = KLUCEL; D = drug =oxybutynin free base ^(b)Mean ± SD (n = 4 skin donors)

These results show that the incorporation of glycerin into the gel hasno measurable impact on the skin permeation of oxybutynin. Therefore,glycerin can be used in a topical oxybutynin gel formulation in order toreduce skin irritation, or for other reasons as will be recognized byone of ordinary skill in the art.

Example 9: Oxybutynin and N-Desethyloxybutynin Plasma Concentrationsafter a Single Application of a 4.4% Oxybutynin Topical Gel Formulationto the Abdomen of Healthy Subjects

A clinical study in 22 healthy volunteers, 19 to 45 years of age,evaluated plasma concentrations of oxybutynin and theN-desethyloxybutynin metabolite after a single topical application ofoxybutynin gel. The study employed a single dose design to evaluate thepharmacokinetics and skin tolerability of a gel formulation foroxybutynin hydrochloride.

Volunteers received a single topical administration of 3 g of 4.4%oxybutynin gel to a 400 cm² area of unbroken skin on the abdomen. Bloodsamples were periodically collected throughout the study period andplasma was harvested according to standard procedures. Plasma oxybutyninand N-desethyloxybutynin metabolite concentrations were estimated usinga high performance liquid chromatography-tandem mass spectrometry methodperformed according to established guidelines.

FIG. 8 shows oxybutynin and N-desethyloxybutynin plasma concentrationsduring the study period. Plasma concentration is indicated on thevertical axis, and time is indicated on the horizontal axis. Afterapplication of the oxybutynin gel, measurable levels of oxybutynin weredetectable in plasma at the first sampling point (2 hours) followingdosing. Mean plasma oxybutynin levels increased steadily during thefollowing 24 hours to a maximum plasma concentration (C_(max)) of 2.17ng/mL. Thereafter plasma drug concentrations decreased with anelimination half-life of approximately 18.45 hours. A second peakapproximately 48 hours after dosing was also apparent.

Measurable levels of N-desethyloxybutynin were detectable in plasma atthe first sampling point (2 hours) following dosing. Mean plasmaN-desethyloxybutynin levels increased steadily during the following 28hours to a C_(max) of 2.20 ng/mL. Thereafter plasma concentrationsdecreased with an elimination half-life of approximately 26.81 hours.Again, a second peak approximately 48 hours after dosing was alsoapparent. The mean AUC ratio for oxybutynin:N-desethyloxybutynin wasabout 0.98:1.

Example 10: Oxybutynin and N-Desethyloxybutynin Plasma Concentrationsafter a Single Application of a 13.2% Oxybutynin Topical Gel Formulationto the Abdomen of Healthy Subjects

A clinical study in 22 healthy volunteers, 19 to 45 years of age,evaluated plasma concentrations of oxybutynin and theN-desethyloxybutynin metabolite after a single topical application ofoxybutynin gel. The study employed a single dose design to evaluate thepharmacokinetics and skin tolerability of a gel formulation foroxybutynin hydrochloride.

Volunteers received a single topical administration of 1 g of 13.2%oxybutynin gel to a 133 cm² area of unbroken skin on the abdomen. Bloodsamples were periodically collected throughout the study period andplasma was harvested according to standard procedures. Plasma oxybutyninand N-desethyloxybutynin metabolite concentrations were estimated usinga high performance liquid chromatography-tandem mass spectrometry methodperformed according to established guidelines.

FIG. 9 shows oxybutynin and N-desethyloxybutynin plasma concentrationsduring the study period. Plasma concentration is indicated on thevertical axis, and time is indicated on the horizontal axis. Afterapplication of the 13.2% gel, measurable levels of oxybutynin weredetectable in plasma at the first sampling point (2 hours) followingdosing. Mean plasma oxybutynin levels increased steadily during thefollowing 26 hours to a Cmax of 1.17 ng/mL. Thereafter plasma drugconcentrations decreased with an elimination half-life of 17.71 hours.As observed with the 4.4% gel formulation in Example 9, a second peakapproximately 48 hours after dosing was also apparent.

Measurable levels of N-desethyloxybutynin were detectable in plasma atthe first sampling point (2 hours) following dosing. Mean plasmaN-desethyloxybutynin levels increased steadily during the following 28hours to a C_(max) of 1.12 ng/mL. Thereafter plasma concentrationsdecreased with an elimination half-life of 19.53 hours. Again, a secondpeak approximately 48 hours after dosing was apparent. The mean AUCratio for oxybutynin:N-desethyloxybutynin was about 1:0.99.

Example 11: Oxybutynin and N-Desethyloxybutynin Plasma Concentrationsafter Single and Repeated Application of an Oxybutynin Topical GelFormulation to the Abdomen of Healthy Subjects

A clinical study in 12 healthy volunteers, 19 to 41 years of age,evaluated plasma concentrations of oxybutynin and theN-desethyloxybutynin metabolite after single and repeated topicalapplications of oxybutynin gel. The study employed a single-period,open-label, multiple dose design to evaluate the pharmacokinetics andskin tolerability of a gel formulation for oxybutynin hydrochloride.

Volunteers received topical administrations of 3 g of 4.4% oxybutyningel on 3 consecutive mornings. Each volunteer received the oxybutyningel administrations on a defined area of unbroken skin on the abdomen.Blood samples were periodically collected throughout the study periodand plasma was harvested according to standard procedures. Plasmaoxybutynin and N-desethyloxybutynin metabolite concentrations wereestimated using high performance liquid chromatography-tandem massspectrometry method performed according to established guidelines.

FIG. 10 shows oxybutynin and N-desethyloxybutynin plasma concentrationsfor the duration of the study period. Plasma concentration is indicatedon the vertical axis, and time is indicated on the horizontal axis.After the initial gel application, low levels of oxybutynin appeared inplasma within one hour following dosing. Mean plasma oxybutynin levelsincreased steadily during the following 24 hours to a mean±SDconcentration of 4.02±2.19 ng/mL at the 24 hour post-dose timepoint.Drug levels measured 24 hours after the second application (4.47±2.38ng/mL) were similar to the initial 24 hour post-dosing levels, butconsiderably higher at the 24 hour post-dose timepoint following thethird application (5.86±3.17 ng/mL). C_(max) occurred 24 hours followinggel application in both assessment periods and was 6.05±3.21 ng/mLfollowing the third application.

A complete characterization of the dosing interval following the thirdapplication showed a drop in oxybutynin concentration for the first 12hours following gel application and then rising again to maximum levelsat the 24 hour timepoint. Plasma oxybutynin decreased steadily for 36hours following the 24 hour timepoint but did not reach baseline duringthe sampling period. This elimination was consistent with an apparenthalf-life of approximately 18 hours, presumably due to a skin depoteffect.

N-desethyloxybutynin kinetics followed a similar pattern as oxybutyninthroughout the study period. However, there appears to be a potentialdiurnal or possibly postural variation in the relationship betweenN-desethyloxybutynin and the parent compound. Initially,N-desethyloxybutynin levels were consistently higher than those of theparent compound following gel application through the 12 hour time pointfrom both applications 1 and 3. However, at subsequent time pointsduring the next 12 hours in both evaluation periods, oxybutynin levelsexceeded N-desethyloxybutynin levels. Thereafter, at each evaluationduring the elimination phase, N-desethyloxybutynin levels were higherthan oxybutynin. The mean AUC ratio for oxybutynin:N-desethyloxybutyninwas 1:0.98.

Example 12: An Evaluation of the Single and Multiple DosePharmacokinetics of Oxybutynin and N-Desethyloxybutynin FollowingAdministration of Oxybutynin Gel in Healthy Volunteers

A clinical study in 20 healthy volunteers, 20 to 44 years of age,evaluated the single and multiple dose pharmacokinetics of oxybutyninand N-desethyloxybutynin following topical oxybutynin geladministration. The study employed a two-period multiple dose study.

In the first treatment period, volunteers received a topicaladministration of 3 g of 4.4% oxybutynin gel followed by a 72 hourevaluation period. The second treatment period, oxybutynin gel wasadministered topically to the volunteers on 7 consecutive mornings. Thetwo treatment periods were separated by a 7-day washout period. Bloodsamples were periodically collected throughout the study periods andplasma was harvested according to standard procedures. Plasma oxybutyninand N-desethyloxybutynin metabolite concentrations were estimated usinghigh performance liquid chromatography-tandem mass spectrometry methodperformed according to established guidelines.

FIG. 11 shows oxybutynin and N-desethyloxybutynin plasma concentrationsfor the duration of the study period. After the initial 3 g oxybutyningel application, measurable levels of oxybutynin were detectable inplasma within two hours following dosing. Mean plasma oxybutynin levelsincreased steadily during the following 24 hours to a C_(max) of 6.35ng/mL. Thereafter plasma drug concentrations decreased in an apparentbiphasic manner with an elimination half-life of approximately 18 hours.Mean plasma N-desethyloxybutynin concentrations followed a similarpattern as the parent compound with a slight lag time, reaching C_(max)(4.50 ng/mL) approximately 26 hours following gel application.

Mean oxybutynin C_(max) and AUC (186 ng·hr/mL) were approximately 18%and 41% higher, respectively, than the mean N-desethyloxybutynin C_(max)and AUC (157 ng·hr/mL). The mean (SD) oxybutynin:N-desethyloxybutyninAUC ratio for the 72 hour treatment period was 1:0.87.

After a 7-day washout following the initial gel application, subjectsapplied daily 3 g doses of oxybutynin gel to rotating body sites(abdomen, upper arms, thighs) for 7 consecutive days. Plasma sampleswere drawn each morning before the next gel application.

Daily morning mean (SD) plasma concentrations were similar following theoutpatient gel applications on Days 10-15, ranging from 4.63 ng/mL to6.15 ng/mL. Following the final gel application, mean plasma oxybutyninconcentrations rose above Time 0 levels (4.63 ng/mL) to a C_(max) of9.01 ng/mL approximately 23 hours after gel application. Mean drugconcentrations decreased during the following 48 hours with anelimination half-life of approximately 24 hours. The average (SD) plasmaconcentration during the 20 hours following the application was 6.22ng/mL.

Mean plasma N-desethyloxybutynin concentrations increased in a moregradual manner and to a lesser extent than the parent compound, reachingmaximum concentration (6.44 ng/mL) for the 0-24 hour interval atapproximately 16 hours. Higher levels were attained following the 24hour timepoint.

Mean oxybutynin C_(max) and AUC (149 ng·hr/mL) were approximately 40%and 19% higher, respectively, than the mean N-desethyloxybutynin C_(max)and AUC (125 ng·hr/mL). The mean (SD) oxybutynin:N-desethyloxybutyninAUC ratio for the first 24 hours of the treatment period was 1:0.87.

Example 13: Single-Dose Pharmacokinetics of Oxybutynin andN-Desethyloxybutynin Following the Application of Topical Oxybutynin Gelto 400 cm² and 800 cm² Application Areas on the Thighs of HealthyVolunteers

A clinical study in 21 healthy volunteers, 21 to 45 years of age,evaluated the effect of application surface area on the single-dosepharmacokinetic of oxybutynin following topical oxybutynin geladministration. The study employed a two-period, open-labeled,randomized crossover design to evaluate the effect of applicationsurface area on the single dose pharmacokinetics and safety of a topicalgel formulation of oxybutynin hydrochloride.

Volunteers received topical administrations of 3 g of 4.4% oxybutyningel at the beginning of two 72 hour treatment periods, with a minimumsix day washout separating the treatment periods. Each volunteerreceived a dose applied to a 400 cm² area in one treatment period, and adose to an 800 cm² area the other treatment period. The sequential orderof the treatment periods was randomized. Blood samples were periodicallycollected throughout the study periods and plasma was harvestedaccording to standard procedures. Plasma oxybutynin andN-desethyloxybutynin metabolite concentrations were evaluated using highperformance liquid chromatography-tandem mass spectrometry methodperformed according to established guidelines.

FIG. 12 shows oxybutynin and N-desethyloxybutynin plasma concentrationsfollowing oxybutynin gel application to a 400 cm² application area forthe duration of the study period. After gel application to the 400 cm²application area, measurable levels of oxybutynin were detectable inplasma at the first sampling timepoint following dosing (2 hours). Meanplasma oxybutynin levels increased steadily to a peak at the 24 hourtimepoint of 2.25 ng/mL. This initial peak was followed by diminishinglevels for approximately 12 hours, followed by a second peak (C_(max))of 3.70 ng/dL at 48 hours post-dose. Thereafter plasma drugconcentrations gradually decreased toward baseline during the following24 hours.

N-desethyloxybutynin levels essentially mimicked those of the parentcompound, with measurable levels of N-desethyloxybutynin appearing bythe 2 hour sampling timepoint. Mean plasma N-desethyloxybutynin levelsincreased to a peak at 28 hours after dosing of 2.21 ng/mL, declined forapproximately 12 hours before increasing to a C_(max) of 2.72 ng/mL at48 hours. The mean (SD) oxybutynin:N-desethyloxybutynin AUC ratio was1:0.91.

FIG. 13 shows oxybutynin and N-desethyloxybutynin plasma concentrationsfollowing oxybutynin gel application to an 800 cm² application area forthe duration of the study period. Plasma oxybutynin andN-desethyloxybutynin concentrations following gel application to an 800cm² surface area produced similar kinetic profiles to the gelapplications made to the 400 cm² area. Both oxybutynin andN-desethyloxybutynin levels were measurable by the 2 hour sampletimepoint and gradually increased during the first 24 hours followingdosing to peaks of 2.92 and 2.39 ng/mL for oxybutynin andN-desethyloxybutynin, respectively. Decreasing levels were observed forapproximately the following 12 hours, followed by a rise to C_(max)(3.80 and 3.40 ng/mL) at 48 hours for both oxybutynin andN-desethyloxybutynin.

Example 14: Topical Oxybutynin Chloride Gel Example 14.1

TABLE 6 Formulation^(a) Et/W/G/D Q_(t) (t = 24 hours) J_(ss) (% w/w)(μg/cm²/t)^(b) (μg/cm²/t)^(b) 74.5/20.0/1.5/4.0 11.37 ± 3.94 0.47 ± 0.1669.5/25.0/1.5/4.0 10.99 ± 4.30 0.45 ± 0.14 64.5/30.0/1.5/4.0 10.02 ±4.49 0.42 ± 0.19 ^(a)Et = ethanol; W = water; G = gelling agent =KLUCEL; D = drug = oxybutynin chloride ^(b)Mean ± SD (n = 4 skin donors)

These results show that a formulation comprising about 65% to about 75%ethanol can be used effectively to delivery oxybutynin in a topicalformulation.

Example 14.2

TABLE 7 Formulation^(a) Et/W/G/D/N Q_(t) (t = 24 hours) J_(ss) pH of gel(% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) 6.0 74.5/18.7/1.5/4.0/1.3 18.94 ±5.12 0.79 ± 0.21 4.6 74.5/20.0/1.5/4.0/0 13.18 ± 4.96 0.55 ± 0.21 ^(a)Et= ethanol; W = water; G = gelling agent = klucel; D = drug = oxybutyninchloride (n = 4 skin donors) N = 2N NaOH ^(b)Mean ± SD (n = 4 skindonors)

These results show that oxybutynin chloride gel with pH 6.0 produceshigher oxybutynin skin permeation than that with pH 4.6. However, it isto be recognized that the formulation having a pH as low as about 4.6provides a desirable flux rate, in certain aspects.

Example 14.3

TABLE 9 Formulation^(a) Et/W/Gl/G/D Q_(t) (t = 24 hours) J_(ss) (% w/w)(μg/cm²/t)^(b) (μg/cm²/t)^(b) 73.2/20.4/0/2.0/4.4 10.66 ± 6.17 0.44 ±0.26 73.2/19.4/1.0/2.0/4.4 10.86 ± 8.62 0.45 ± 0.36 ^(a)Et = ethanol; W= water; Gl = glycerin; G = gelling agent = klucel; D = drug =oxybutynin chloride ^(b)Mean ± SD (n = 4 skin donors)

These results show that presence of glycerin in the oxybutynin chloridegel does not affect oxybutynin skin permeation through the skin.Therefore, glycerin can be included in an oxybutynin gel formulation asan emollient or other additive for reducing skin irritation or for otherintended purposes that will be recognized by those skilled in the art.

Example 15: Topical Oxybutynin Chloride and Free Base Gel

TABLE 9 Formulation^(a) Et/W/E/G/D₁/D₂ Q_(t) (t = 24 hours) J_(ss)Enhancer (% w/w) (μg/cm²/t)^(b) (μg/cm²/t)^(b) None63.8/30.0/0/2.0/2.2/2.0 25.85 ± 15.35 1.08 ± 0.64 Triacetin58.8/30.0/5.0/2.0/2.2/2.0 41.77 ± 27.99 1.74 ± 1.17 ^(a)Et = ethanol; E= enhancer; W = water; G = gelling agent = KLUCEL; D₁ = drug =oxybutynin chloride; D₂ = drug = oxybutynin free base ^(b)Mean ± SD (n =4 skin donors)

These results show that triacetin significantly increases the skin fluxof total oxybutynin as compared to the gel formulation withouttriacetin.

Example 16: Topical Oxybutynin Chloride Gel and Flux Over Time Data

A free form oxybutynin chloride gel was prepared having a composition of73.3 wt % ethanol, 18.0 wt % water, 1.0 wt % glycerin, 2.0 wt % KLUCELHF, 4.4 wt % oxybutynin chloride, and 1.3 wt % sodium hydroxide. Theresulting gel had a pH of 6. Nine separate skin samples were tested forflux over a period of 48 hours and the results are shown in Table 10.After 24 hours of sampling, the remaining gel on the top of the skin wasremoved and then the 30 hour samples (6 hours after gel removal) and 48hour samples (24 hours after gel removal) were taken.

TABLE 10 Mean Cumulative Permeation Time Sample 6 hr 24 hr 30 hr 48 hr 11.42 ± 2.01  4.57 ± 1.53  8.20 ± 0.40 11.95 ± 2.14  2 9.41 ± 0.58 19.61± 6.71 31.82 ± 7.37 46.43 ± 8.72  3 4.59 ± 2.68 14.12 ± 7.17 16.15 ±9.81 24.77 ± 11.83 4 3.90 ± 1.23  9.40 ± 4.27 14.84 ± 6.70 26.47 ± 14.345 3.99 ± 3.28 16.17 ± 6.05 26.43 ± 7.89 38.35 ± 9.74  6 1.44 ± 0.43 3.70 ± 0.67  5.66 ± 1.06 8.75 ± 1.60 7 3.03 ± 0.45  7.39 ± 1.89 10.03 ±2.66 15.17 ± 4.25  8 6.62 ± 1.51 17.23 ± 3.24 27.27 ± 8.93 42.98 ± 18.029 4.20 ± 0.95 13.73 ± 3.06 20.49 ± 4.52 32.19 ± 5.50  Mean 4.29 ± 2.5011.77 ± 5.72 17.84 ± 9.20 27.45 ± 13.65

In one aspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 1.5to about 7.0 ug/cm2/hr at about 6 hrs after application. In anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 6 toabout 17 ug/cm2/hr at about 24 hrs after application. In yet anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 8 toabout 27 ug/cm2/hr at about 30 hrs after application. In yet anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 14to about 40 ug/cm2/hr at about 48 hrs after application. In anotheraspect, an oxybutynin gel formulation for topical application isprovided that delivers oxybutynin at a mean flux rate of from about 1.5to about 7.0 ug/cm2/hr at about 6 hrs after application; from about 6 toabout 17 ug/cm2/hr at about 24 hrs after application; from about 8 toabout 27 ug/cm2/hr at about 30 hrs after application; and from about 14to about 40 ug/cm2/hr at about 48 hrs after application. The oxybutynincan be present as a free base or as a pharmaceutically acceptable salt(e.g., such as HCl) or a mixture thereof. In yet another aspect, theoxybutynin can be present as its R-isomer or S-isomer, or theirpharmaceutically acceptable salts or mixtures thereof. When theoxybutynin is present as its corresponding isomer, in some aspects, themean flux rates for that isomer may be as following: from about 0.7 toabout 5.0 ug/cm2/hr at about 6 hrs after application; from about 3 toabout 9 ug/cm2/hr at about 24 hrs after application; from about 4 toabout 14 ug/cm2/hr at about 30 hrs after application; from about 6 toabout 25 ug/cm2/hr at about 48 hrs after application.

The above flux rates deliver therapeutic levels of oxybutynin to asubject in need thereof. Such therapeutic plasma levels may range fromabout 1.4 ng/ml to about 8 ng/ml, and in certain aspects, the plasmaconcentration may range from about 1.42 ng/ml to about 4 ng/ml. Inanother aspect, the plasma concentration may range from about 1.8 ng/mlto about 4 ng/ml. In yet another aspect, the plasma concentration mayrange from about 1.8 ng/ml to about 3 ng/ml.

Example 17: Topical Oxybutynin Cream

A free form oxybutynin cream containing the compositions in each phaseas shown in Table 11 may be produced. Oxybutynin is present in theformulation at from about 1 to about 10% w/w.

TABLE 11 Phase Component % w/w Water Water 20-60  Propylene Glycol 1-10Sodium Stearoyl Lactate 0-5  20% PLURONIC 270 0-50 Methyl Paraben  0-0.5Oil Oleic Acid 0-20 Cetyl Alcohol 0-20 Glycerol Monooleate 0-10 LaurylAcetate 0-10 Propyl Paraben  0-0.5

Example 18: Topical Oxybutynin Lotion

A free form oxybutynin lotion containing the compositions in each phaseas shown in Table 12 may be produced. Oxybutynin is present in theformulation at from about 1 to about 10% w/w.

TABLE 12 Phase Component % w/w Water Water 20-90 Distearyl DimoniumChloride 1-5 Sodium Chloride 0-5 Methyl Paraben  0-0.5 Oil Glycerin 0-20 Petrolatum  0-10 Isopropyl Palmitate 0-5 Cetyl Alcohol  0-10Dimethicone 0-5 Propyl Paraben 0.0.5

Example 19: Topical Oxybutynin Emulsified Gel

A free form oxybutynin gel containing the compositions in each phase asshown in Table 13 may be produced. Oxybutynin is present in theformulation at from about 1 to about 10% w/w. A free form oxybutynin gelmay be produced using an emulsified gel carrier. Oxybutynin is presentin the formulation from about 1 to about 20% w/w. Based on the forgoing,it is expected that the pH effects shown in the other applicableexamples can be observed in certain aspects of these formulations.Further, the emulsified gel bases are expected to deliver oxybutynineither in its free base form, in the form of a pharmaceuticallyacceptable salt, or in a mixture thereof, analogous to the above-recitedexamples, with delivery rates equivalent thereto. In addition, it is tobe understood that oxybutynin can be present in its R- or S-isomericforms.

TABLE 13 Phase Component % w/w Water Water 30-90  Propylene Glycol 1-10Oil Sodium Stearoyl Lactate 0-5  20% PLURONIC 270 0-20 Silicone Dioxide0-1  Methyl Paraben  0-0.5 CARBOPOL 0.1-5   Oleic Acid 0-10 CetylAlcohol 0-10 Glycerol Monooleate 0-10 Lauryl Acetate 0-10 Propyl Paraben 0-0.5

Example 20: Topical Oxybutynin Ointment

A free form oxybutynin ointment containing the compositions in eachphase as shown in Table 14 may be produced.

TABLE 14 Component % w/w Cholesterol 0-5  Stearyl Alcohol 0-5  White Wax0-10 White Petrolatum 70-100 Oxybutynin 1-10

Example 21: Oxybutynin Free Form Gel Containing Optical Isomers

Table 15 shows the skin flux measured over a 24 hour period for each ofthe R and S isomers in the chloride and free base forms. Both oxybutyninfree base and oxybutynin chloride are chiral molecules that exists intwo forms, R and S and were each tested in their optically pure formsaccording to the present invention as shown in Table 15.

TABLE 15 Formulation^(a) Formulation^(a) Et/W/Gl/G/D₁/N Et/W/Gl/G/D₂/H(% w/w) (% w/w) 73.2/17.9/1.0/2.0/4.4/1.5 73.2/18.3/1.0/2.0/4.0/1.5Q_(t) (t = 24 hours) (μg/cm²/t)^(b) R-Oxybutynin 6.98 ± 4.26 7.08 ± 5.43S-Oxybutynin 6.24 ± 3.77 6.87 ± 5.35 ^(a)Et = ethanol; W = water; G =gelling agent = KLUCEL; Gl = glycerin D₁ = oxybutynin chloride; D₂ =oxybutynin free base N = 2N sodium hydroxide (NaOH); H = 2HHydrochloride (HCl) ^(b)Mean ± SD (n = 3 skin donors)

These results show that the R and S isomers from both oxybutynin freebase gel and oxybutynin chloride gel permeate through the skin in equalamounts. Further, these results show that oxybutynin chloride can bedelivered at about the same rate as oxybutynin free base from atopically applied unoccluded gel.

It is to be understood that the above-described compositions and modesof application are only illustrative of preferred embodiments of thepresent invention. Numerous modifications and alternative arrangementsmay be devised by those skilled in the art without departing from thespirit and scope of the present invention and the appended claims areintended to cover such modifications and arrangements.

Thus, while the present invention has been described above withparticularity and detail in connection with what is presently deemed tobe the most practical and preferred embodiments of the invention, itwill be apparent to those of ordinary skill in the art that numerousmodifications, including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

1.-27. (canceled)
 28. A method of treating a human patient with an overactive bladder comprising the step of applying an unoccluded oxybutyningel formulation once a day to the outer skin surface of the humanpatient's chest, abdomen, upper arms and/or thighs, wherein theunoccluded oxybutynin gel formulation comprises: (i) 10 to 132 mg ofoxybutynin; (ii) water; (iii) a gelling agent; and (iv) a solvent, andwherein a single dose application of the unoccluded oxybutynin gelformulation to the outer skin surface of the human patient's chest,abdomen, upper arms and/or thighs produces a mean plasma area under thecurve (AUC) ratio of oxybutynin to N-desethyloxybutynin of from about0.5:1 to about 5:1, and a mean N-desethyloxybutynin plasma level ofabout 0.5 ng/ml to about 8 ng/ml.
 29. The method of claim 28 wherein thesingle dose application of the unoccluded oxybutynin gel formulationproduces a mean (R)—N-desethyloxybutynin plasma level of about 0.25ng/ml to about 4 ng/ml.
 30. The method of claim 28 wherein following thesingle dose application of the unoccluded oxybutynin gel formulation,the mean AUC ratio of oxybutynin to N-desethyloxybutynin is from about0.5:1 to about 4:1.
 31. The method of claim 28 wherein following thesingle dose application of the unoccluded oxybutynin gel formulation,the mean AUC ratio of oxybutynin to N-desethyloxybutynin is from about0.8:1 to about 2.5:1.
 32. The method of claim 28 wherein the single doseapplication applies about 1 gram to about 3 grams of the unoccludedoxybutynin gel formulation.
 33. The method of claim 28 wherein thesingle dose is applied over an area of the outer skin of about 133 cm²to about 800 cm².
 34. The method of claim 28 wherein the oxybutynin isselected from the group consisting of oxybutynin free base, oxybutyninchloride, or a mixture of oxybutynin free base and oxybutynin chloride.35. The method of claim 28 wherein unoccluded oxybutynin gel formulationcomprises about 1 wt % to about 30 wt % water; about 0.05 wt % to about10 wt % of the gelling agent; and at least 40 wt % of a solvent.
 36. Themethod of claim 28 wherein the unoccluded oxybutynin gel formulationfurther comprises additional components selected from the groupconsisting of emulsifiers, chelating agents, surfactants, emollients,preservatives, antioxidants, lubricants, pH adjusters, dyes andperfumes.
 37. The method of claim 28 wherein the unoccluded oxybutyningel formulation further comprises a permeation enhancer, an emollient, apH additive, or a combination thereof.
 38. The method of claim 28wherein the unoccluded oxybutynin gel formulation comprises: (i) about 4wt % to about 13.2 wt % of oxybutynin free base, oxybutynin chloride ora mixture of oxybutynin free base and oxybutynin chloride; (ii) about0.1 wt % to about 5 wt % of a gelling agent; and (iii) about 65 wt % toabout 80 wt % of a solvent selected from the group consisting ofethanol, isopropanol, propanol, methanol, and mixtures thereof; and (iv)about 1 wt % to about 30 wt % water, and wherein the formulation has apH of from about pH 6.0 to about pH 10.0.
 39. A method of treating ahuman patient with an over active bladder comprising the step ofapplying an unoccluded oxybutynin gel formulation once a day to theouter skin surface of the human patient's chest, abdomen, upper armsand/or thighs, wherein the unoccluded oxybutynin gel formulationcomprises: (i) 10 to 132 mg of oxybutynin; (ii) about 1 wt % to about 30wt % water; (iii) about 0.1 wt % to about 5 wt % of a gelling agent;(iv) at least 40 wt % of a solvent selected from ethanol, isopropanol,benzyl alcohol, propanol, methanol, other C₄-C₁₀ mono-alcohols andmixtures thereof; wherein a single dose application of the unoccludedoxybutynin gel formulation to the outer skin surface of the humanpatient's chest, abdomen, upper arms and/or thighs produces a meanplasma area under the curve (AUC) ratio of oxybutynin toN-desethyloxybutynin of from about 0.5:1 to about 4:1; a meanN-desethyloxybutynin plasma level of about 0.5 ng/ml to about 8 ng/mland a mean (R)—N-desethyloxybutynin plasma level is about 0.25 ng/ml toabout 4 ng/ml.
 40. The method of claim 39 wherein the single doseapplication of the unoccluded gel formulation provides a mean AUC ratioof oxybutynin to N-desethyloxybutynin of from about 0.8:1 to about2.5:1.
 41. The method of claim 39 wherein the single dose applicationapplies about 1 gram to about 3 grams of the unoccluded oxybutynin gelformulation.
 42. The method of claim 39 wherein the single dose isapplied over an area of the outer skin of about 133 cm² to about 800cm².
 43. The method of claim 39 wherein the oxybutynin is selected fromthe group consisting of oxybutynin free base, oxybutynin chloride, or amixture of oxybutynin free base and oxybutynin chloride.
 44. The methodof claim 39 wherein the unoccluded oxybutynin gel formulation furthercomprises additional components selected from the group consisting ofemulsifiers, chelating agents, surfactants, emollients, preservatives,antioxidants, lubricants, pH adjusters, dyes, and perfumes.
 45. Themethod of claim 39 wherein the unoccluded oxybutynin gel formulationcomprises: (i) about 4 wt % to about 13.2 wt % of oxybutynin free base,oxybutynin chloride or a mixture of oxybutynin free base and oxybutyninchloride; (ii) about 0.1 wt % to about 5 wt % of a gelling agent; and(iii) about 65 wt % to about 80 wt % of a solvent selected from thegroup consisting of ethanol, isopropanol, propanol, methanol, andmixtures thereof; and (iv) about 1 wt % to about 30 wt % water; andwherein the formulation has a pH of from about pH 6.0 to about pH 10.0.46. A method of treating a human patient with an over active bladdercomprising the step of applying about 1 to about 3 grams of anunoccluded oxybutynin gel formulation once a day to the outer skinsurface of the human patient's chest, abdomen, upper arms and/or thighs,wherein, the unoccluded oxybutynin gel formulation comprises: (i) 10 to132 mg of oxybutynin wherein the oxybutynin is oxybutynin free base,oxybutynin chloride or a mixture of oxybutynin free base and oxybutyninchloride; (ii) about 1 wt % to about 30 wt % water; (iii) about 0.1 wt %to about 5 wt % of a gelling agent; (iv) about 65 wt % to about 80 wt %of a solvent selected from the group consisting of ethanol, isopropanol,propanol, methanol, and mixtures thereof; wherein a single doseapplication of the unoccluded oxybutynin gel to 133 cm² to 800 cm² ofthe outer skin surface of the human patient's chest, abdomen, upper armsand/or thighs produces a mean plasma area under the curve (AUC) ratio ofoxybutynin to N-desethyloxybutynin of from about 0.8:1 to about 2.5:1; amean N-desethyloxybutynin plasma level of from about 0.5 ng/ml to about5 ng/ml; and a mean (R)—N-desethyloxybutynin plasma level of from about0.25 ng/ml to about 4 ng/ml.
 47. The method of claim 46 wherein theunoccluded oxybutynin gel formulation further comprises additionalcomponents selected from the group consisting of emulsifiers, chelatingagents, surfactants, emollients, preservatives, antioxidants,lubricants, pH adjusters, dyes, and perfumes.